Hetaryl styryl quinolines as leukotriene inhibitors

ABSTRACT

Compounds having the formula: ##STR1## are leukotriene antagonists and inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents.

CROSS-REFERENCE

This is a division of Ser. No. 527,236, filed May 22, 1990, now U.S.Pat. No. 5,104,882, which is a continuation-in-part of Ser. No. 356,478,filed May 24, 1989, now abandoned, which is a continuation-in-part ofSer. No. 275,160, filed Nov. 22, 1988, now abandoned, which is acontinuation-in-part of Ser. No. 125,050, filed Nov. 25, 1987, nowabandoned.

BACKGROUND OF THE INVENTION

The leukotrienes and their biological activities, especially their rolesin various disease states and conditions have been described. Forexample, see U.S. Pat. No. 4,683,325 (Jul. 28, 1987), which isincorporated herein by reference.

Several classes of compounds exhibit ability to antagonize the action ofleukotrienes in mammals, especially humans. See for example: UK2,058,785 and 2,094,301; and EP 56,172, 61,800, and 68,739.

EP 110,405 (Jun. 13, 1984) describes anti-inflammatory and antiallergicsubstituted benzenes which are disclosed to be leukotriene inhibitors,i.e., inhibitors of the 5-lipoxygenase pathway.

SUMMARY OF THE INVENTION

The present invention relates to compounds having activity asleukotriene and SRS-A antagonists or inhibitors of the biosynthesis ofthe leukotrienes, to methods for their preparation, to intermediatesuseful in their preparation and to methods and pharmaceuticalformulations for using these compounds in mammals (especially humans).

Because of their activity as leukotriene antagonists or biosynthesisinhibitors, the compounds of the present invention are useful asanti-asthmatic, anti-allergic, and anti-inflammatory agents and areuseful in treating allergic rhinitis and chronic bronchitis and foramelioration of skin diseases like psoriasis and atopic eczema. Thesecompounds are also useful to antagonize or inhibit the pathologicactions of leukotrienes on the cardiovascular and vascular systems forexample, actions such as result in angina. The compounds of the presentinvention are useful in the treatment of inflammatory and allergicdiseases of the eye, including allergic conjunctivitis. The compoundsare also useful as cytoprotective agents.

Thus, the compounds of the present invention may also be used to treator prevent mammalian (especially, human) disease states such as erosivegastritis; erosive esophagitis; inflammatory bowel disease;ethanol-induced hemorrhagic erosions; hepatic ischemic; noxious agentinduced damage or necrosis of hepatic, pancreatic, renal, or myocardialtissue; liver parenchymal damage caused by hepatoxic agents such as CCl₄and D-galactosamine; ischemic renal failure; disease-induced hepaticdamage; bile salt induced pancreatic or gastric damage; trauma- orstress-induced cell damage; and glycerol-induced renal failure.

DETAILED DESCRIPTION

The compounds of this invention are best realized by Formula I: ##STR2##wherein R¹ is H, halogen C₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₂ -C₈ alkynyl,--CF₃, --SR², --S(O)R², --S(O)₂ R², --NR³ R³, --Or³, --COOR³, --(C═O)R³,--C(OH)R³ R³, --CN, --NO₂, --N₃, substituted or unsubstituted phenyl,substituted or unsubstituted benzyl, substituted or unsubstituted2-phenethyl, or substituted or unsubstituted pyridyl;

R² is C₁ 14 C₈ alkyl, C₂ -C₈ alkenyl, C₂ -C₈ alkynyl, --CF₃, substitutedor unsubstituted phenyl, substituted or unsubstituted benzyl, orsubstituted or unsubstituted 2-phenethyl;

R³ is H or R² ;

R⁴ is H, halogen, --NO₂, --CN, --OR³, --SR³, NR³ R³, or C₁ -C₈ alkyl;

CR³ R⁴ may be the radical of a naturally occurring amino acid;

R⁵ is H, halogen, --NO₂, --N₃, --CN, --SR², --NR³ R³, --OR³, C₁ -C₈alkyl, --(C═O)R³, or --S(O)₂ R² ;

R⁶ is --(CH₂)_(s) --C(R⁷ R⁷)--(CH₂)_(s) --R⁸ or --CH₂ CONR¹² R¹² ;

R⁷ is H or C₁ -C₄ alkyl;

R⁸ is

A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N, Sor O and with each ring in the heterocyclic radical being formed of 5 or6 atoms, or

B) the radical W--R⁹ ;

R⁹ contains up to 21 carbon atoms and is (1) a hydrocarbon radical or(2) an acyl radical of an organic acyclic or monocyclic carboxylic acidcontaining not more than 1 heteroatom in the ring;

R¹⁰ is --SR¹¹, --OR¹², --NR¹² R¹² ;

R¹¹ is C₁ -C₆ alkyl, --(C═O)R¹⁴, substituted or unsubstituted phenyl, orsubstituted or unsubstituted benzyl;

R¹² is H, R¹¹, adamantyl, naphthyl, halogen-substituted C₁ -C₆ alkyl, C₁-C₆ alkylene-OR³, or two R¹² groups joined to the same N may form a ringof 5 or 6 members containing up to two heteroatoms chosen O, S or N;

R¹³ is C₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₂ -C₈ alkynyl, --CF₃, orunsubstituted phenyl, benzyl, or 2-phenethyl;

R¹⁴ is H or R¹³ ;

R¹⁵ is R³ or halogen;

R¹⁶ is H, C₁ -C₄ alkyl, or OH;

R¹⁷ is C₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₂ -C₈ alkynyl, or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl;

5R¹⁸ is C₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₂ -C₈ alkynyl, --CF₃, orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl;

R¹⁹ is C₄ -C₈ alkyl, C₂ -C₈ alkenyl, C₂ -C₈ alkynyl, --CF₃, substitutedphenyl, or unsubstituted phenyl, benzyl, or 2-phenethyl;

R²⁰ is H or R¹⁷ ;

m and m' are independently 0-8;

n and n' are independently 0 or 1 but not both 0;

p and p' are independently 0-8;

m+n+p is 1-10 when X² is O, S, S(O), or S(O)₂ ;

m+n+p is 0-10 when X² is CR³ R¹⁶ ;

m'+n'+p' is 1-10 when X³ is O, S, S(O), or S(O)₂ ;

m'+n'+p' is 0-10 when X³ is CR³ R¹⁶ ;

r is 0 or 1 when Z¹ is HET (--R³, --R⁵);

r is 1 when Z¹ is --CONR³ or when n=0;

r' is 0 or 1 when Z² is HET(--R³, --R⁵);

r' is 1 when Z² is CONR³ or when n'=0;

s is 0-3;

Q¹ and Q² are independently --COOR³, tetrazole, methyltetrazole,--COOR⁶, --CONHS(0)₂ R¹³, --CN, --CONR¹² R¹², --CHO, --CH₂ OH, --COCH₂OH, --NR⁷ S(O)₂ R¹³ ; --C(O)R¹⁹, --NR²⁰ C(O)OR¹⁷, --NR¹² C(O)NR¹² R¹²,--NR⁷ C(O)R¹⁸, --OC(O)NR¹² R¹², --S(O)₂ R¹⁸, --S(O)R¹⁸, --S(O)₂ NR¹²R¹², --NO₂, S-substituted phenyl, ##STR3## or if Q¹ or Q² is COOH and R⁴is --OH, --SH, or --NHR³ then Q¹ or Q² and R⁴ and the carbons throughwhich they are attached may form a heterocyclic ring by loss of water;

W is O, S, or NR³ ;

X¹ is O, S, --S(O)--, --S(O)₂ --, --NR³, or --CR³ R³ --;

X² and X³ are independently O, S, S(O), S(O)₂, or CR³ R³ --;

X² and X³ are independently O, S, S(O), S(O)₂,

X² and X³ are independently O, S, S(O), S(O)₂, or CR³ R¹⁶ ;

Y is --CR³ ═CR³ --, --C═C--, --CR³ R³ R³ --X¹, --X¹ --CR³ R³ --, --CR³R³ --X¹ --CR³ R³ --, ##STR4## Z¹ and Z² are independently --CONR³ -- or--HET(--R³ --R⁵)--, provided that at least one of them is --HET(--R³,--R⁵)--;

HET is ##STR5## and the pharmaceutically acceptable salts thereof.

Alkyl, alkenyl, and alkynyl are intended to include linear, branched,and cyclic structures and combinations thereof.

As used herein, the term "alkyl" includes "loweralkyl" and extends tocover carbon fragments having up to 20 carbon atoms. Examples of alkylgroups include octyl, nonyl, norbornyl, undecyl, dodecyl, tridecyl,tetradecyl, pentadecyl, eicosyl, 3,7-ethyl-2,2-methyl-4-propylnonyl,cyclododecyl, adamantyl, and the like.

As used herein, the term "loweralkyl" includes those alkyl groups offrom 1 to 7 carbon atoms. Examples of loweralkyl groups include methyl,ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl,heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,2-methylcyclopropyl, cyclopropylmethyl, and the like.

Alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl,heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,1-propenyl, 2-butenyl, 2-methyl-2-butenyl and the like.

As used herein, the term "alkoxy" includes those alkoxy groups of from 1to 3 carbon atoms of either a straight, branched, or cyclicconfiguration. Examples of alkoxy groups include methoxy, ethoxy,propoxy, isopropoxy, cyclopropyloxy, and the like.

Substituted phenyl, benzyl, 2-phenethyl and pyridyl include 1 or 2substituents on the aromatic ring selected from C₁ -C₆ alkyl, R¹⁰, NO₂,SCF₃, halogen, --COR⁷, --COR¹⁰, CN, and CF₃.

Halogen includes F, Cl, Br and I.

The prodrug esters of Q (i.e., when Q=--COOR⁶) are intended to includethe esters such as are described by Saari et al., J. Med. Chem., 21, No.8, 746-753 (1978), Sakamoto et al., Chem. Pharm. Bull., 32, No. 6,2241-2248 (1984) and Bundgaard et al., J. Med. Chem., 30, No. 3,451--454 (1987).

When Q and R⁴ and the carbons through which they are attached form aring, the rings thus formed include lactones, lactams, and thiolactones.

It is intended that the definitions of any substituent (e.g., R¹, R², m,Q, X, etc.) in a particular molecule be independent of its definitionselsewhere in the molecule. Thus, --NR³ R³ represents --NHH, --NHCH₃,--NHC₆ H₅, etc.

The heterocycles formed when two R¹² groups join through N includepyrrolidine, piperidine, morpholine, thiamorpholine, piperazine, andN-methylpiperazine.

The naturally occurring amino acids, the radicals of which may be CR³R⁴, include alanine, asparagine, aspartic acid, arginine, cysteine,glutamic acid, glutamine, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine and valine.

Some of the compounds described herein contain one or more centers ofasymmetry and may thus give rise to diastereoisomers and opticalisomers. The present invention is meant to comprehend such possiblediastereoisomers as well as their racemic and resolved, optically activeforms. Optically active (R) and (S) isomers may be resolved usingconventional techniques.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Preferred compounds of Formula I are those wherein:

R¹ is H, halogen, C₁ -C₈ alkyl, --CF₃, --SR², --S(O)R², --S(O)₂ R²,--OR³, or --CN;

R² is C₁ -C₈ alkyl or --CF₃ ;

R³ is H or R² ;

R⁴ is H, --OR³, --SR³, NR³ R³, or C₁ -C₈ alkyl;

CR³ R⁴ may be the radical of a naturally occurring amino acid;

R⁵ is H, halogen, --CN, --SR², --OR³, C₁ -C₈ alkyl, or --(C═O)R³ ;

R⁶ is --(CH₂)_(s) --C(R⁷ R⁷)--(CH₂)_(s) --R⁸ or --CH₂ CONR¹² R¹² ;

R⁷ is H or C₁ -C₄ alkyl;

R⁸ is

A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N, Sor O and with each ring in the heterocyclic radical being formed of 5 or6 atoms, or

B) the radical W--R⁹ ;

R⁹ contains up to 21 carbon atoms and is (1) a hydrocarbon radical or(2) an acyl radical of an organic acyclic or monocyclic carboxylic acidcontaining not more than 1 heteroatom in the ring;

R¹⁰ is --SR¹¹, --OR¹², or --NR¹² R¹² ;

R¹¹ is C₁ -C₆ alkyl, --(C═O)R¹⁴, unsubstituted phenyl, or unsubstitutedbenzyl;

R¹² is H, R¹¹, or two R¹² groups joined to the same N may form a ring of5 or 6 members containing up to two heteroatoms chosen from O, S or N;

R¹³ is C₁ -C₈ alkyl, --CF₃, or unsubstituted phenyl, benzyl, or2-phenethyl;

R¹⁴ is H or R¹³ ;

R¹⁵ is R³ or halogen;

R¹⁶ is H, C₁ -C₄ alkyl, or OH;

m and m' are independently 0-4;

n and n' are independently 0 or 1 but not both 0;

p and p' are independently 0-4;

m+n+p is 1-10 when X² is O or S;

m+n+p is 0-10 when X² is CR³ R¹⁶ ;

m'+n'+p' is 1-10 when X³ is O or S;

m'+n'+p' is 0-10 when X³ is CR³ R¹⁶ ;

r is 0 or 1 when Z¹ is HET (--R³, --R⁵);

r is 1 when Z¹ is --CONR³ ;

r' is 0 or 1 when Z² is HET(--R³, --R⁵);

r' is 1 when Z² is CONR³ ;

s is 0-3;

Q¹ and Q² are independently --COOR³, tetrazole, --COOR⁶, --CONHS(O)₂R¹³, --CONR¹² R¹², --NHS(O)₂ R¹³ ; or if Q¹ or Q² is COOH and R⁴ is--OH, --SH, or --NHR³ then Q¹ or Q² and R⁴ and the carbons through whichthey are attached may form a heterocyclic ring by loss of water;

W is O, S, or NH;

X¹ is O, S, --NR³, or --CR³ R³ --;

X² and X³ are independently O, S, or CR³ R¹⁶ ;

Y is --CR³ ═CR³ --, --C═C--, --CR³ R³ --X¹ --, or --X¹ --CR³ R³ --;

Z¹ and Z² are independently --CONR³ -- or --HET(--R³ --R⁵)-- providedthat at least one of them is --HET(--R³, --R⁵)--;

HET is ##STR6## and the pharmaceutically acceptable salts thereof.

More-preferred compounds of Formula I are those wherein:

CR³ R⁴ is not the radical of a naturally occurring amino acid;

Q¹ and Q² are independently --COOR³, tetrazole or --CONR¹² R¹² ;

Y is --CH═CH--;

Z¹ and Z² are --HET(--R³ --R⁵)--;

and the remainder of the definitions are as in the above preferredembodiment.

Another more-preferred group of compounds of Formula I are those ofFormula Ia: ##STR7## wherein: R⁴ is H or C₁ -C₈ alkyl;

CR³ R⁴ is not the radical of a naturally occurring amino acid;

m is 1-4;

m' is 0-4;

p' is 0-4;

r' is 0 or 1;

Q¹ and Q² are independently --COOR³, tetrazole, --CONHS(O)₂ R¹³, or--CONR¹² R¹² ;

X³ is S or CR³ R¹⁶ ;

Y is --CH═CH-- or --CH₂ O--;

and the remainder of the definitions are as in the above preferredembodiment.

Another preferred embodiment of the invention is compounds of Formula Iof the Formula Ib: ##STR8## wherein R¹ is halogen,

R⁵ is H, halogen, --CN, --SR², --S(O)₂ R², or --OR² ;

R⁷ is H₇ or C₁ -C₄ alkyl;

R²¹ is R⁷ or --O--C₁ -C₄ alkyl;

r' 0 or 1;

m' is 0-2;

p' is 0 or 1;

Q² is as defined for Formula I;

X³ is S or CH₂ ; and

Y is --CH₂ CH₂ --, --CH═CH-- or --CH₂ 0--.

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula I are meant toalso include the pharmaceutically acceptable salts and the lactone,lactam and thiolactone forms.

The compounds of Formula I are active as antagonists of SRS-A andespecially of leukotriene D₄. These compounds also have modestinhibitory activity on leukotriene biosynthesis but are primarily oftherapeutic interest as antagonists. The activity of the compounds ofFormula I can be detected and evaluated by methods known in the art. Seefor example, Kadin, U.S. Pat. No. 4,296,129.

The ability of the compounds of Formula I to antagonize the effects ofthe leukotrienes and to inhibit the biosynthesis of the leukotrienesmakes them useful for inhibiting the symptoms induced by theleukotrienes in a human subject. The compounds are valuable therefore inthe prevention and treatment of such disease states in which theleukotrienes are the causative factor, e.g. skin disorders, allergicrhinitis, and obstructive airway diseases. The compounds areparticularly valuable in the prevention and treatment of allergicbronchial asthma. They are also effective in the treatment ofinflammatory diseases of the eye.

The cytoprotective activity of a compound may be observed in bothanimals and man by noting the increased resistance of thegastrointestinal mucosa to the noxious effects of strong irritants, forexample, the ulcerogenic effects of aspirin or indomethacin. In additionto lessening the effect of non-steroidal anti-inflammatory drugs on thegastrointestinal tract, animal studies show that cytoprotectivecompounds will prevent gastric lesions induced by oral administration ofstrong acids, strong bases, ethanol, hypertonic saline solutions and thelike.

Two assays can be used to measure cyto-protective ability. These assaysare; (A) an ethanol-induced lesion assay and (B) an indomethacin-inducedulcer assay and are described in U.S. Pat. No. 4,683,325 Jul. 28, 1987).

The leukotriene antagonist properties of compounds of the presentinvention were evaluated using the following assays.

Guinea-Pig Ileum Preparation for Evaluation of Antagonists ofLeukotriene D₄ and Other Mediators Tissue

Sections of ileum were taken from male Hartley strain guinea pigs(Charles River, U.S.A.) 300 to 500 g which were sacrificed by a blow tothe head and exsanguinated. Terminal ileum was removed, cleaned withwarm Tyrode's solution and then divided into segments of approximately1.5-2.0 cm in each. The segments of ileum were then mounted under 1 gtension in a 20 ml organ bath containing 10 ml of Tyrode's solution withthe following composition (mM): NaCl, 137; KCl, 2.7; MgSO₄ ·7H₂ O, 0.8;CaCl₂, 1.8; NaH₂ PO₄, 0.42; NaHCO₃, 11.9; Dextrose, 5.6. The bathingsolution was continuously aerated with 95% O₂ and 5% CO₂ and bathtemperature was maintained at 37° C. The beta-adrenoceptor blocker,timolol (0.5 μg/ml) and the antimuscarinic agent atropine (1.0 μM) werepresent in the Tyrode's solution. Isometric tension changes wererecorded using Grass FT03 force displacement transducers (GrassInstrument G., Quincy, Mass.) connected to a Beckman Type R Dynograph.The output (analog) signals from all channels of the Beckman Dynographwere converted to digital signals (DL-12 Data Logger, BuxcoElectronics). These signals were subsequently fed into an IBM-XTcomputer for storage and subsequent analysis (Buxco Electronics CustomSoftware). In order to wash the tissue, the bath solution wasautomatically aspirated and replaced with a constant volume (10 ml) offresh solution by means of timer controlled solenoid valves.

Antagonist Testing

After the tissues were stable a standard dose of 0.3 ng/ml LTD₄ (100 μl)was repeatedly added (timer controlled Harvard Pump) to the bath every4.5 minutes (1 minute contact, 30 second wash, 3 minute rest) until aconsistent response was obtained (minimum of 4 responses). Addition ofLTD₄ was performed automatically with two 4-channel Harvard ApparatusSyringe Pumps which delivered 100 μl (final bath concentration 0.3ng/ml) of agonist simultaneously to all tissues every 4.5 minutes.Following each addition of LTD₄ the tissue was washed with Tyrode'ssolution until baseline tension was re-established. After consistentresponses were obtained the tissues were used to screen compounds.

Usually, 10 μl of a 10 mg/ml solution of the compound to be tested wasadded to the bath 30 seconds prior to the addition of LTD₄. The compoundand LTD₄ remained in contact with the tissue until the maximum tensionwas developed (1 minute) after which the tissue was washed repeatedlyuntil the baseline was re-established. Percent inhibition relative tothe immediately preceding control response was computed on an IBM-XT foreach dose of test compound (Buxco Electronics Custom Software). If thecompound was active (greater than 50% inhibition) then tests wereperformed with 10 fold serial dilutions until inhibition was less than50%. Provided the response was inhibited by less than 20%, the tissuewas used immediately to evaluate another compound. When the response wasinhibited by greater than 20%, cycles of LTD₄ alone were added until aconsistent response was re-established.

In order to determine the specificity of the active compounds, they weretested against contractions induced by a standard dose of histamine (50ng/ml) using a similar protocol to that described above (1/2 minutecontact time, 30 seconds wash and 2 minutes rest).

LTD₄ Binding

The results for LTD₄ binding were determined by the method of S. S. Pongand R. N. DeHaven, Proc. Nat. Acad. Sci. USA, 80, 7415-7419 (1983).

Compounds of Formula I were tested using the following assay todetermine their mammalian leukotriene biosynthesis inhibiting activity.

Rat Peritoneal Polymorphonuclear (PMN) Leukocyte Assay

Rats under ether anesthesia are injected (i.p.) with 8 ml of asuspension of sodium caseinate (6 grams in ca. 50 ml water). After 15-24hr. the rats are sacrificed (CO₂) and the cells from the peritonealcavity are recovered by lavage with 20 ml of buffer (Eagles MEMcontaining 30 mM HEPES adjusted to pH 7.4 with NaOH). The cells arepelleted (350× g, 5 min), resuspended in buffer with vigorous shaking,filtered through lens paper, recentrifuged and finally suspended inbuffer at a concentration of 10 cells/ml. A 500 μl aliquot of PMNsuspension and test compound are preincubated for 2 minutes at 37° C.,followed by the addition of 10 μM A-23187. The suspension is stirred foran additional 4 minutes then bioassayed for LTB₄ content by adding analiquot to a second 500 μl portion of the PMN at 37° C. The LTB₄produced in the first incubation causes aggregation of the second PMN,which is measured as a change in light transmission. The size of theassay aliquot is chosen to give a submaximal transmission change(usually -70%) for the untreated c formation is calculated from theratio of transmission change in the sample to the transmission change inthe compound-free control.

The following assays can be used to evaluate compounds which are eitherleukotriene antagonists or inhibitors of leukotriene biosynthesis orwhich possess a combination of these two properties.

Antigen Challenge `in vitro` Assay

Male guinea pigs weighing 300-350 g are sensitized by injecting(intraperitoneally) 0.5 ml of a suspension containing 0.4 mg of eggalbumin (Ovalbumin, Grade V, Sigma Chemical Co.) and 4.0 g of aluminumhydroxide in 19.6 ml of saline. Two weeks are permitted forsensitization to occur.

Three sensitized guinea pigs are stunned and exanguinated. The tracheasare removed, freed of adhering tissue and divided longitudinally bycutting through the cartilaginous tissue directly opposite the muscleinsertion. Each opened trachea is then transected between every secondcartilage. Four of the cut sections are tied together, end to end, in aseries with No. 7 silk thread ensuring that the tracheal muscles are allin the same vertical plane. Thus, each chain consists of tissue fromthree different animals.

The chain so formed is then suspended under 1 g of tension (by silk tiesat each end) in a 20 ml organ bath containing 10 ml of modified¹Krebs-Henseleit buffer solution gassed with 95% O₂ and 5% CO₂ at 37° C.Mepyramine (7×10⁻⁶ M), atropine (1×10⁻⁷ M) and indomethacin (1.4×10⁻⁶ M)are added to the buffer to block the response to released histamine,acetylcholine, and cyclooxygenase products. To record responses, one endof the tracheal chain is attached to a Gould-Statham UC-2 forcedisplacement transducer which is connected to a Beckman Type RDynograph. The preparations are allowed to equilibrate for one hourduring which time the tissues are automatically washed (10 ml volumedisplacement) every 6 minutes.

After the equilibration period the tissues are primed with methacholine(10 μg/ml), washed and allowed to recover to baseline. The tissues aretreated again with a second dose of methacholine, washed, allowed toreturn to baseline and washed for an additional hour.

Two chains are used as a control. These are incubated in a concentrationof egg albumin (0.1 μg/ml) sufficient to induce an average contractionof 50-80% of the methacholine response.

Each compound to be tested is added (at a final bath concentration of 10μg/ml) 20 minutes prior to challenging the tissue with egg albumin.

The response of the challenged tissue is expressed as a percentage ofthe methacholine maximum. The percentage inhibition for each compound isthen calculated. Compounds which at 10 μg/ml (final concentration)inhibit the egg albumin response by 50% or more are retested at a lowerconcentration.

Asthmatic Rat Assay

Rats are obtained from an inbred line of asthmatic rats. Both female(190-250 g) and male (260-400 g) rats are used.

Egg albumin (EA), grade V, crystallized and lyophilized, is obtainedfrom Sigma Chemical Co., St. Louis. Aluminum hydroxide is obtained fromthe Regis Chemical Company, Chicago. Methysergide bimaleate is suppliedby Sandoz Ltd., Basel.

The challenge and subsequent respiratory recordings are carried out in aclear plastic box with internal dimensions 10×6×4 inches. The top of thebox is removable; in use, it is held firmly in place by four clamps andan airtight seal is maintained by a soft rubber gasket. Through thecenter of each end of the chamber a Devilbiss nebulizer (No. 40) isinserted via an airtight seal and each end of the box also has anoutlet. A Fleisch No. 0000 pneumotachograph is inserted into one end ofthe box and coupled to a Grass volumetric pressure transducer (PT5-A)which is then connected to a Beckman Type R Dynograph throughappropriate couplers. While aerosolizing the antigen, the outlets areopen and the pneumotachograph is isolated from the chamber. The outletsare closed and the pneumotachograph of the respiratory patterns. Forchallenge, 2 ml of a 3% solution of antigen in saline is placed intoeach nebulizer and the aerosol is generated with air from a small Potterdiaphragm pump operating at 10 psi and flow of 8 liters/minute.

Rats are sensitized by injecting (subcutaneously) 1 ml of a suspensioncontaining 1 mg EA and 200 mg aluminum hydroxide in saline. They areused between days 12 and 24 postsensitization. In order to eliminate theserotonin component of the response, rats are pretreated intravenously 5minutes prior to aerosol challenge with 3.0 μg/kg of methysergide. Ratsare then exposed to an aerosol of 3% EA in saline for exactly 1 minute,then their respiratory profiles are recorded for a further 30 minutes.The duration of continuous dyspnea is measured from the respiratoryrecordings.

Compounds are generally administered either orally 1-4 hours prior tochallenge or intraveneously 2 minutes prior to challenge. They areeither dissolved in saline or 1% methocel or suspended in 1% methocel.The volume injected is 1 ml/kg (intraveneously) or 10 ml/kg (orally).Prior to oral treatment rats are starved overnight. Their activity isdetermined in terms of their ability to decrease the duration ofsymptoms of dyspnea in comparison with a group of vehicle-treatedcontrols. Usually, a compound is evaluated at a series of doses and anED₅₀ is determined. This is defined as the dose (mg/kg) which wouldinhibit the duration of symptoms by 50%.

The magnitude of a prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to the age,weight and response of the individual patient. In general, the dailydose range for anti-asthmatic, anti-allergic or anti-inflammatory useand generally, uses other than cytoprotection, lie within the range offrom about 0.001 mg to about 100 mg per kg body weight of a mammal,preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to 1mg per kg, in single or divided doses. On the other hand, it may benecessary to use dosages outside these limits in some cases.

The exact amount of a compound of the Formula I to be used as acytoprotective agent will depend on, inter alia, whether it is beingadministered to heal damaged cells or to avoid future damage, on thenature of the damaged cells (e.g., gastrointestinal ulcerations vs.nephrotic necrosis), and on the nature of the causative agent. Anexample of the use of a compound of the Formula I in avoiding futuredamage would be co-administration of a compound of the Formula I with anon-steroidal anti-inflammatory drug (NSAID) that might otherwise causesuch damage (for example, indomethacin). For such use, the compound ofFormula I is administered from 30 minutes prior up to 30 minutes afteradministration of the NSAID. Preferably it is administered prior to orsimultaneously with the NSAID, (for example, in a combination dosageform).

The effective daily dosage level for compounds of Formula I inducingcytoprotection in mammals, especially humans, will generally range fromabout 0.1 mg/kg to about 100 mg/kg, preferably from about 1 mg/kg toabout 100 mg/kg. The dosage may be administered in single or dividedindividual doses.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicbases or acids and organic bases or acids.

Salts derived from inorganic bases include aluminum, ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic, manganous,potassium, sodium, zinc salts and the like. Particularly preferred arethe ammonium, calcium, magnesium, potassium, and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as arginine, betaine, caffeine, choline,N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric and p-toluenesulfonic acid, andthe like. Particularly preferred are hydrobromic, hydrochloric,phosphoric, and sulfuric acids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like.

For use where a composition for intravenous administration is employed,a suitable dosage range for anti-asthmatic, anti-inflammatory oranti-allergic use is from about 0.001 mg to about 10 mg (preferably fromabout 0.01 mg to about 1 mg) of a compound of Formula I per kg of bodyweight per day and for cytoprotective use from about 0.1 mg to about 100mg (preferably from about 1 mg to about 100 mg and more preferably fromabout 1 mg to about 10 mg) of a compound of Formula I per kg of bodyweight per day.

In the case where an oral composition is employed, a suitable dosagerange for anti-asthmatic, anti-inflammatory or anti-allergic use is,e.g. from about 0.01 mg to about 100 mg of a compound of Formula I perkg of body weight per day, preferably from about 0.1 mg to about 10 mgper kg and for cytoprotective use from about 0.1 mg to about 100 mg(preferably from about 1 mg to about 100 mg and more preferably fromabout 10 mg to about 100 mg) of a compound of Formula I per kg of bodyweight per day.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or a nebuliser, or as a powder which may beformulated as a cartridge from which the powder composition may beinhaled with the aid of a suitable device. The preferred delivery systemfor inhalation is a metered dose inhalation (MDI) aerosol, which may beformulated as a suspension or solution in fluorocarbon propellants.

Suitable topical formulations of Compound I include transdermal devices,aerosols, creams, ointments, lotions, dusting powders, and the like.

For the treatment of diseases of the eye, ophthalmic preparations forocular administration comprising 0.001-1% by weight solutions orsuspensions of the compounds of Formula I in an acceptable opthalmicformulation may be used.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719, thedisclosures of which are hereby incorporated herein by reference.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient, as a powder or granules or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet may be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet contains from about 2.5 mg toabout 500 mg of the active ingredient and each cachet or capsulecontains from about 2.5 to about 500 mg of the active ingredient.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I:

    ______________________________________                                        Injectable Suspension (I.M.)                                                                          mg/ml                                                 Compound of Formula I   10                                                    Methylcellulose         5.0                                                   Tween 80                0.5                                                   Benzyl alcohol          9.0                                                   Benzalkonium chloride   1.0                                                   Water for injection to a total volume of 1 ml                                 Tablet                  mg/tablet                                             Compound of Formula I   25                                                    Microcrystalline Cellulose                                                                            415                                                   Providone               14.0                                                  Pregelatinized Starch   43.5                                                  Magnesium Stearate      2.5                                                                           500                                                   Capsule                 mg/capsule                                            Compound of Formula I   25                                                    Lactose Powder          573.5                                                 Magnesium Stearate      1.5                                                                           600                                                   ______________________________________                                    

In addition to the compounds of Formula I, the pharmaceuticalcompositions of the present invention can also contain other activeingredients, such as cyclooxygenase inhibitors, non-steroidalanti-inflammatory drugs (NSAIDs), peripheral analgesic agents such aszomepirac, diflunisal and the like. The weight ratio of the compound ofthe Formula I to the second active ingredient may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the Formula I is combined with an NSAID the weight ratio of thecompound of the Formula I to the NSAID will generally range from about1000:1 to about 1:1000. Combinations of a compound of the Formula I andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

NSAIDs can be characterized into five groups:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives; and

(5) the oxicams

or a pharmaceutically acceptable salt thereof. NSAIDs which are withinthe scope of this invention are those disclosed in U.S. Pat. No.4,683,325 (Jul. 28, 1987).

Pharmaceutical compositions comprising the Formula I compounds may alsocontain inhibitors of the biosynthesis of the leukotrienes such as aredisclosed in U.S. Pat. No. 4,666,907 (Apr. 19, 1987), U.S. Pat. No.4,663,307 (May 5, 1987), U.S. Pat. No. 4,611,056 (Sept. 9, 1986), andU.S. Pat. No. 4,634,766 (Jan. 6, 1987), which are hereby incorporatedherein by reference.

The compounds of the Formula I may also be used in combination withleukootriene antagonists such as those disclosed in EP 106,565 (Apr. 25,1984) and EP 104,885 (Apr, 4, 1984) which are hereby incorporated hereinby reference and others known in the art such as those disclosed in EP56,172 (Jul. 21, 1982) and U.S. Pat. No. 4,424,231 (Jan. 3, 1984); andin U.K. Patent Specification No. 2,058,785, which are herebyincorporated herein by reference.

Pharmaceutical compositions comprising the Formula I compounds may alsocontain as the second active ingredient prostaglandin (includingthromboxane) antagonists such as those disclosed in U.S. Pat. No.4,536,507 (Aug. 20, 1985), U.S. Pat. No. 4,237,160 (Dec. 2, 1980), EP166,597 (Jan. 1, 1986), and EP 234,708 (Sep. 2, 1987). They may alsocontain histidine decarboxylase inhibitors such asα-fluoromethylhistidine, described in U.S. Pat. No. 4,325,961. Thecompounds of the Formula I may also be advantageously combined with anH₁ or H₂ -receptor antagonist, such as for instance benadryl, dramamine,histadyl, phenergan, terfenadine, acetamazole, cimetidine, ranitidine,famotidine, aminothiadiazoles disclosed in EP 40,696 (Dec. 2, 1981) andlike compounds, such as those disclosed in U.S. Pat. Nos. 4,283,408;4,362,736; and 4,394,508. The pharmaceutical compositions may alsocontain a K⁺ /H⁺ ATPase inhibitor such as omeprazole, disclosed in U.S.Pat. No. 4,255,431, and the like. Another useful pharmaceuticalcomposition comprises the Formula I compounds in combination withserotonin antagonists such as methysergide, the serotonin antagonistsdisclosed in Nature, vol. 316, pages 126-131, 1985, and the like. Eachof the references referred to in this paragraph is hereby incorporatedherein by reference.

When the second active ingredient in compositions of this invention is athromboxane synthetase inhibitor, such inhibitor can be as described inUK 2,038,821 (e.g., UK-37248 and dazoxiben hydrochloride), U.S. Pat. No.4,217,357 (e.g., UK-34787), U.S. Pat. No. 4,444,775 (e.g., CGS 13080),U.S. Pat. No. 4,226,878 (e.g., ONO 046), U.S. Pat. No. 4,495,357 (e.g.,U63557A) U.S. Pat. No. 4,273,782 (e.g., UK-38485), or EP 98,690 (e.g.,CV-4151).

The combination compositions can be administered orally or or other thanorally; e.g., parenterally, by insufflation, topically, rectally, etc.;using appropriate dosage forms; e.g., tablets, capsules, suspensions,solutions, and the like, for oral administration; suspension emulsions,and the like, for prenteral administration; solutions for intravenousadministration; and ointments, transdermal patches, and the like, fortopical administration. These compositions are formulated similarly tothe compositions discussed above.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The following compounds (formula I') are within the scope of theinvention:

                                      TABLE 1                                     __________________________________________________________________________     ##STR9##                                                    I'               Example                                                                             R.sup.1                                                                              Y        A                B                                      __________________________________________________________________________     1    7-Cl   CHCH     S(CH.sub.2).sub.2 CO.sub.2 H                                                                   CH.sub.2 CH.sub.2 (1,2-Phe)CO.sub.2                                            H*                                     2    7-Cl   CHCH     S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        CH.sub.2 CH.sub.2 (1,2-Phe)CO.sub.2                                            H                                      3    7-Cl   CH.sub.2 CH.sub.2                                                                      S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (1,3-Phe)CO.sub.2 H                     4    7-Cl   CHCH     S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (2,5-Thio)CO.sub.2 H                    5    7-Cl   CHCH     S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (1,3-Phe)CO.sub.2 H                     6    7-Cl   CHCH     S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (1,4-Phe)CO.sub.2 H                     7    7-Cl   CHCH     S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (1,3-Phe)CO.sub.2 H                     8    7-Cl   CHCH     S(1,3-Phe)CO.sub.2 H                                                                           (CH.sub.2).sub.2 CH(CH.sub.3)CH.sub                                           .2 CO.sub.2 H                           9    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (1,3-Phe)CO.sub.2 H                    10    7-Cl   CHCH     S(1,3-Phe)CO.sub.2 H                                                                           (1,3-Phe)CO.sub.2 H                    11    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)NH-t-Bu                                                                  (1,3-Phe)CO.sub.2 H                    12    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (3,5-Pye)CO.sub.2 H                    13    7-Cl   CHCH     S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (3,5-Pye)CO.sub.2 H                    14    7-Cl   CH.sub.2 O                                                                             S(1,3-Phe)CO.sub.2 H                                                                           S(1,3-Phe)CO.sub.2 H                   15    7-Cl   CHCH     S(1,3-Phe)CO.sub.2 H                                                                           S(1,3-Phe)CO.sub.2 H                   16    7-Cl   CHCH     S(1,4-Phe)CO.sub.2 H                                                                           S(1,4-Phe)CO.sub.2 H                   17    7-Cl   CHCH     S(1,4-Phe)CO.sub.2 H                                                                           (2,6-Pye)CO.sub.2 H                    18    7-OCH.sub.3                                                                          CHCH     S(CH.sub.2 ).sub.2 CO.sub.2 H                                                                  (1,3-Phe)CO.sub.2 H                    19    6-CF.sub.3                                                                           CHCH     S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (1,3-Phe)CO.sub.2 H                    20    7-CF.sub.3                                                                           CHCH     S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (1,4-Phe)CO.sub.2 H                    21    6-SO.sub.2 CH.sub.3                                                                  CHCH     S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (1,3-Phe)CO.sub.2 H                    22    H      CHCH     S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (1,3-Phe)CO.sub.2 H                    23    7-Cl   CHCH     S(1,4-Phe)CO.sub.2 H                                                                           (1,3-Phe)CO.sub.2 H                    24    7-Cl   CHCH     S(1,4-Phe)C(O)N)(CH.sub.3).sub.2                                                               (1,3-Phe)CO.sub.2 H                    25    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   CH.sub.2 (1,3-Phe)CO.sub.2 H           26    7-Cl   CHCH     S(4,2-Pye)CO.sub.2 H                                                                           (1,3-Phe)CO.sub.2 H                    27    7-Cl   CHCH     S(1,2-Phe)CO.sub.2 H                                                                           (1,3-Phe)CO.sub.2 H                    28    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)CO.sub.2                                            H                                      29    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)NMe.sub. 2                                                               (CH.sub.2).sub.2 (1,2-Phe)CO.sub.2                                            H                                      30    7-Cl   CH.sub.2 O                                                                             S(1,2-Phe)CO.sub.2 H                                                                           S(1,2-Phe)CO.sub.2 H                   31    7-Cl   CH.sub.2 O                                                                             (CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                         (1,3-(4-ClPhe))CO.sub.2 H              32    7-Cl   CH.sub.2 O                                                                             SCH.sub.2 (1,2-Phe)CO.sub.2 H                                                                  SCH.sub.2 (1,2-Phe)CO.sub.2 H          33    7-Cl   CH.sub.2 O                                                                             SCH.sub.2 (1,2-Phe)CO.sub.2 H                                                                  S(CH.sub.2).sub.2 C(O)N(CH.sub.3).s                                           ub.2                                   34    7-Cl   CHCH     S(CH.sub.2).sub.3 C(O)N(CH.sub.3).sub.2                                                        (1,3-Phe)CO.sub.2 H                    35    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)NH-t-Bu                                                                  (CH.sub.2).sub.2 (1,2-Phe)CO.sub.2                                            H                                      36    7-Cl   CH.sub.2 CH.sub.2                                                                      S(CH.sub.2).sub.2 C(O)NH-t-Bu                                                                  (CH.sub.2).sub.2 (1,2-Phe)CO.sub.2                                            H                                      37    7-Cl   CH.sub.2 CH.sub.2                                                                      S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (CH.sub.2).sub.2 (1,3-Phe)CO.sub.2                                            H                                      38    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)N(CH.sub.2).sub.2                                                        (1,2-Phe)CO.sub.2 H                    39    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)NH(1-adamantyl)                                                          (CH.sub.2).sub.2 (1,2-Phe)CO.sub.2                                            H                                      40    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (CH.sub.2).sub.2 (1,2-Phe)CN.sub.4                                            H*                                     41    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (CH.sub.2).sub.2 (1,2-Phe)CH.sub.2                                            CN.sub.4 H                             42    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (CH.sub.2).sub.2 (1,2-Phe)CH.sub.2                                            CO.sub.2 H                             43    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           44    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (1,3-Phe)CH.sub.2 CN.sub.4 H           45    7-Cl   CH.sub.2 O                                                                             S(1,3-Phe)CO.sub.2 H                                                                           (1,3-Phe)CO.sub.2 H                    46    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (1,3-Phe)CH.sub.2 C(O)N(CH.sub.3).s                                           ub.2                                   47    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (1,3-Phe)CH.sub.2 C(O)NH-t-Bu          48    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CN.sub.4 H                                                                   (1,3-Phe)CH.sub.2 C(O)N(CH.sub.3).s                                           ub.2                                   49    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CN.sub.4 H                                                                   (1,3-Phe)CH.sub.2 C(O)NH-t-Bu          50    7-Cl   CH.sub.2 O                                                                             SCH.sub.2 C(O)N(CH.sub.3).sub.2                                                                (1,3-Phe)CH.sub.2 CN.sub.4 H           51    7-Cl   CH.sub.2 O                                                                             SCH.sub.2 C(O)NH-t-Bu                                                                          (1,3-Phe)CH.sub.2 CN.sub.4 H           52    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (1,2-Phe)CH.sub.2 CN.sub.4 H           53    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)NH-t-Bu                                                                  (1,2-Phe)CH.sub.2 CN.sub.4 H           54    7-Cl   CH.sub.2 O                                                                             SCH.sub.2 CO.sub.2 H                                                                           (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           55    7-Cl   CH.sub.2 O                                                                             SCH.sub.2 CO.sub.2 H                                                                           (CH.sub.2).sub.2 (1,2-Phe)C(O)NH-t-                                           Bu                                     56    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,3-Phe)C(O)N(CH.                                           sub.3).sub.2                           57    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,3-Phe)C(O)NH-t-                                           Bu                                     58    7-Cl   CH.sub. 2 O                                                                            SCH.sub.2 CO.sub.2 H                                                                           (CH.sub.2).sub.2 (1,3-Phe)C(O)N(CH.                                           sub.3).sub.2                           59    7-Cl   CH.sub.2 O                                                                             SCH.sub.2 CO.sub.2 H                                                                           (CH.sub.2).sub.2 (1,3-Phe)C(O)NH-t-                                           Bu                                     60    7-Cl   CH.sub.2 O                                                                             SCH.sub.2 CN.sub.4 H                                                                           (CH.sub.2).sub.2 (1,3-Phe)C(O)N(CH.                                           sub.3).sub.2                           61    7-Cl   CH.sub.2 O                                                                             SCH.sub.2 CN.sub.4 H                                                                           (CH.sub.2).sub.2 (1,3-Phe)C(O)NH-t-                                           Bu                                     62    H      CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           63    6,7-diCl                                                                             CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           64    7-S(O).sub.2 Me                                                                      CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           65    6-OCH.sub.3                                                                          CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           66    6-CH(CH.sub.3).sub.2                                                                 CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2                                                              (1,2-Phe)C(O)N(CH.sub.3).sub.2         67    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)NH-t-                                           Bu                                     68    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.2).sub.5 *                         69    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)N((CH                                           .sub.2).sub.2 O(CH.sub.2).sub.2)*      70    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)NH-l-                                           adamantyl                              71    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)NHCH.                                           sub.2 Ph*                              72    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)NH-l-                                           naphthyl                               73    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CN.sub.4 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           74    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CN.sub.4 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)NH-t-                                           Bu                                     75    7-Cl   CH.sub.2 O                                                                             SCH.sub.2 CH(CH.sub. 3)CO.sub.2 H                                                              (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           76    7-Cl   CH.sub.2 O                                                                             SCH.sub.2 CH(CH.sub.3)CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,2-Phe)C(O)NH-t-                                           Bu                                     77    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-(4-BrPhe))C(O                                           )N(CH.sub.3).sub.2                     78    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-(4-SCH.sub.3                                            he))C(O)N(CH.sub.3).sub.2              79    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-(4-S(O).sub.2                                            CH.sub.3 Phe))C(O)N(CH.sub.3).sub.                                           2                                      80    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-(5-BrPhe))C(O                                           )N(CH.sub.3).sub.2                     81    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-(5-SCH.sub.3                                            he))C(O)N(CH.sub.3).sub.2              82    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-(5-S(O).sub.2                                            CH.sub.3 Phe))C(O)N(CH.sub.3).sub.                                           2                                      83    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (CH.sub.2).sub.2 (1,2-Phe)C(O)NHS(O                                           ).sub.2 CH.sub.3                       84    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)NHS(O).sub.2 CF.sub.3                                                    (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           85    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (1,3-Phe)CH.sub.2 C(O)NHS(O).sub.2                                            Ph                                     86    7-Cl   CH.sub.2 O                                                                             OCH.sub.2 CN.sub.4 N                                                                           (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           87    7-Cl   CH.sub.2 O                                                                             OCH.sub.2 CO.sub.2 H                                                                           (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           88    7-Cl   CH.sub.2 O                                                                             OCH(CH.sub.3)CO.sub.2 H                                                                        (CH.sub.2).sub.2 (1,2                                                         Phe)C(O)N(CH.sub.3).sub.2              89    7-Cl   CH.sub.2 O                                                                             O(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (1,3-Phe)CH.sub.2 CN.sub.4 H           90    7-Cl   CH.sub.2 O                                                                             O(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                                                        (1,3-Phe)CH(CH.sub.3)CN.sub.4 H        91    7-Cl   CH.sub.2 CH.sub.2                                                                      S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub. 3).sub.2                          92    7-Cl   CH.sub.2 CH.sub.2                                                                      SCH.sub.2 CH(CH.sub.3)CO.sub.2 H                                                               (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           93    7-Cl   CH.sub.2 CH.sub.2                                                                      SCH.sub.2 CO.sub.2 H                                                                           (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           94    7-Cl   CH.sub.2 CH.sub.2                                                                      SCH(CH.sub.3)CO.sub.2 H                                                                        (CH.sub.2).sub.2 (1,2-Phe)C(O)N(CH.                                           sub.3).sub.2                           95    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)N(C.s                                           ub.2 H.sub.5).sub.2                    96    7-Cl   CH.sub.2 O                                                                             S(CH.sub.2).sub.2 CO.sub.2 H                                                                   (CH.sub.2).sub.2 (1,2-Phe)C(O)NHCH.                                           sub.3                                  __________________________________________________________________________     ##STR10##                                                                     ##STR11##                                                                     ##STR12##                                                                     ##STR13##                                                                     ##STR14##                                                                     ##STR15##                                                                     tBu = C(CH.sub.3).sub.3                                                       ##STR16##                                                                

Compounds of the present invention can be prepared according to thefollowing methods. Temperatures are in degrees Celcius.

METHOD A

Quinaldine derivative II is condensed with aldehyde IIa in the presenceof a suitable catalyst like ZnCl₂ at temperatures greater than 120° orby heating with a dehydrating agent such as acetic anhydride to giveadduct III. Bromo acid IV is treated with 2 equivalents of a base suchas n-butyllithium in a suitable solvent such as THF at -100° then at-78° with III to afford alcohol V. Alcohol V is reacted with thiol VI inthe presence of a suitable catalyst such as BF₃ or AlCl₃ to give adductVII.

Method B

Alternatively adduct V can be transformed to VIII, where Z is a suitableleaving group such as Cl, using reaction conditions such as CCl₄/trioctylphosphine. VIII is reacted with thiol VI in the presence of asuitable base such as K₂ CO₃ to give adduct VII.

METHOD C

Referring to Method C, a quinoline derivative of structure IX isprepared from II using a suitable reagent such as N-bromosuccinimide. IXis then reacted with a compound of formula X in the presence of asuitable base such as NAOH, NaH, K₂ CO₃ or NaOMe in an inert solventsuch as THF with warming if necessary to provide the adduct XI. Usingthe reactions described in Methods A or B Adduct XI is transformed toXII.

METHOD D

Referring to Method D, bromo derivative XIII can be treated with PPh₃ ina suitable solvent such as toluene or CH₃ CN with warming if necessaryto provide phosphonium salt XIV. The phosphonium salt XIV is treatedwith n-butyllithium then with lactol XV to afford styrene adduct XVI.Alcohol XVI in transformed to ester XVII using conventional methods suchas CrO₃ /pyridine followed by MnO₂ /NaCN/AcOH/MeOH. Styrene adduct XVIIis condensed with thiol VI in the presence of a suitable catalyst suchas AlCl₃ to give thiol ether XVIII.

When A=CN, XVIII is reduced with a reagent such as SnCl₂ /HCl to givealdehyde XIX. Quinaldine derivative IX is treated with PPh₃ in asuitable solvent such as toluene to give phosphonium salt XX. Thephosphonium salt XX is treated with n-butyl lithium then with aldehydeXIX to give styryl quinoline XXI.

When A=OMe, XVIII is dimethylated using a suitable reagent such as BBr₃to give phenol derivative XXII. Phenol XXII is condensed with quinaldinederivative IX using a suitable catalyst such as K₂ CO₃ to afford adductXXIII.

METHOD E

Referring to Method E, quinaldine derivative II is first treated withLDA and then with bromo derivative XXIV to afford adduct XXV. Cyanoderivative XXV is reduced to aldehyde XXVI with a reagent such as SnCl₂/HCl. Using the methodology described in Method A or B XXVI is convertedto XXVII.

METHOD F

Reaction of styrylaldehyde III with an alkanoic acid or tetrazolesubstituted with a thiol or hydroxy group in an inert solvent such asbenzene in the presence of a suitable catalyst such as BF₃.OEt affordsthe styrylquinoline derivative XXX.

The groups Q¹ and Q² may be modified by hydrolysis of an ester group,removal of a blocking group, or conversion of a nitrile to an amide ortetrazole by heating with tributyltin azide, thus providing additionalexamples of the leukotriene antagonists of the present invention.Compound XXX is representative of the structure I compounds.

METHOD G

Other compounds of Formula I can be prepared as indicated in Method G.Thus the ester derivative XXXI can be reduced to the alcohol XXXII bylithium aluminum hydride or other suitable reducing agents. AlcoholXXXII can then be oxidized to aldehyde XXXII by pyridiniumchlorochromate or other suitable oxidizing agents. Carboxylic acids ofFormula XXXIa can be converted to the acid chloride XXXIV (the acidbromide or a mixed carbonate anhydride could also be used) which whenreacted with diazomethane yields the diazoketone XXXV. Compound XXXV,upon reaction with aqueous acid, preferably a nonnucleophilic acid suchas sulfuric acid or p-toluenesulfonic acid, is converted to thehydroxymethyl ketone XXXVI.

Acid chloride XXXIV, upon reaction with a sulfonamide, R¹³ SO₂ NH₂, inthe presence of a weak base yields the acyl-sulfonamide XLII. Reactionof XXXIV with an amine, R¹² R¹² NH, yields amide XXXVII. Amide XXXVIIcan be sequentially reduced, to amine XXXVIII, with diborane or lithiumaluminum hydride, and sulfonylated with R¹³ SO₂ Cl to producesulfonamide XXXIX. Amide XXXVII (when both R¹² substituents arehydrogen) can be dehydrated by standard reagents to nitrile XL, which isconverted to tetrazole XLI by reaction with sodium azide, tri-n-butyltinazide or other suitable methods.

METHOD H

Compound XI is converted to phosphonium salt XLII by the followingsequence of reactions: 1) reduction of the carbonyl group to an alcoholby means of a suitable reducing agent such as NaBH₄ or LiBH₄ ; 2)conversion of the alcohol to a bromide with an appropriate reagentcombination such as 1,2-bis(diphenylphosphino)ethane/CBr₄ ; 3) reactionof the bromide with triphenylphosphine. A Wittig olefination reactionbetween XV and XLII, using a base such as potassium hexamethyldisilazide(KHMDS), yields compound XLIII. Alcohol XLIII is converted to amide XLIVby the sequence: 1) oxidation to the aldehyde using MnO₂ in EtOAc; 2)oxidative conversion of the aldehyde to the methyl ester using MnO₂/NaCN/AcOH/MeOH/THF; 3) treatment of the resulting ester with an amineHNR¹² R¹² or an aluminum amide such as (CH₃)₂ AlNR¹² R¹² yields amideXLIV. Reaction of XLIV and VI as described in Method D then yieldscompound XLV.

METHOD I

Compound XVII is converted to amide XLVI by one of the methods describedin Methods G and H. Hydration of the double bond in XLVI is effected bysequential treatment with Hg(OAc)₂ and NaBH₄ to yield compound XLVII.Reaction of XLVII with alcohol XLIX, using a catalyst such as ZnCl₂ thenyields compound L. An alternate synthesis of XLVII involves, firsthydration of XVII to XLVIII, followed by amide formation. Compound L canalso be prepared by acid-catalyzed addition of XLIX to the double bondin XLVI. Methods of hydration and of alcohol addition to double bondsare described in J. March, Advanced Organic Chemistry, 3rd. ed., JohnWiley & Sons, New York, 1985, pp. 681-687.

It is to be noted that intermediate XLVIII may form a seven-memberedring lactone between the alcohol group and the ester group. Such alactone can also be used to form amide XLVII.

Compound L is transformed to compounds LI or LII by the methodologydescribed in Method D.

METHOD J

The functional groups, representative of Q¹ or Q², which are present inintermediates V, XVI, XVII, XVIII, XIX, XXII, XLIII, XLIV, XLVI, XLVII,XLVIII and L can be transformed to other representatives of Q¹ or Q² bythe methodology described in Method G. These transformed intermediatescan also be employed, according to the above methods, to preparecompounds of Formula I.

It will be evident to one skilled in the art that the above describedmethods must be compatible with the other functional groups present inthe molecules. Where necessary, such compatibility is achieved bysuitable protection and deprotection techniques (see for example, T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, NewYork, 1981).

METHOD K

The enol acetate of LIII is obtained by heating LIII in isopropenylacetate in the presence of an acid. Ozolysis of this enol ester yieldsthe aldehyde LIV. Starting from a bromophenol, protection of the alcoholand addition of a reagent such as butyllithium, lithium or magnesiumaffords the organometallic LV, which is reacted with LIV to give thehydroxyacid LVI. At this point, the acid can be converted to an ester(R² I/base), an amide (from the ester by treatment with Me₂ AlNR¹² R¹²),a nitrile (formation of RCONH₂ and dehydration with trifluoroaceticanhydride/pyridine) or a ketone (addition of R² Li at 0° C. andquenching with TMSCl). Deprotection of the phenol is then done by usinga reagent such as tetrabutylammonium fluoride in the case of silyl etheror pyridinium p-toluenesulfonate when P is a 2-tetrahydropyranyl group.Reaction of the phenol with a 2-(bromomethyl)quinoline (IX) derivativein the presence of K₂ CO₃ yields the hydroxyketone LVII. The benzylicalcohol is then reacted with methanesulfonyl chloride in the presence ofa base such as triethylamine and the mesylate so obtained is displacedby the sodium or the cesium thiolate of VI to afford LVIII.Alternatively, the benzylic alcohol LVII can be displaced by the thiolVI in the presence of a Lewis acid such as BF₃ ·Et₂ O or AlCl₃ to giveLVIII. Finally, the groups Q¹ and Q² of LVIII can be converted to othergroups as in methods G or J as follows: an ester can be hydrolyzed tothe acid; a nitrile can be reacted with tributyltin azide to afford atetrazole; an oxime can be obtained from a ketone by treatment withhydroxylamine hydrochloride; an amide can be obtained from an acid asalready described or from an ester by reaction with NR¹² R¹² AlMe₂ ; anitrile can be obtained from an ester by treatment with Me₂ AlNH₂ at ca.80° C.; a carbamate can be obtained from a benzoic acid by reaction withdiphenylphosphoryl azide and R¹⁷ OH; and an aniline amide or asulfonamide can be obtained by first forming the aniline from a benzoicacid by reaction with diphenylphophoryl azide/Et₃ N or isobutylchloroformate/sodium azide and second, acylation or sulfonylation ofthis aniline derivative with R¹⁸ COCl or a sulfonic anhydride.

METHOD L

The hydroxyacid LVI is cyclized to the lactone LIX using a reagent suchas 2-chloro-N-methylpyridinium iodide. Deprotection of the phenol andcoupling with IX as in Method K affords lactone LIX. The lactone can beconverted to an hydroxyacid (hydrolysis with NaOH), an hydroxyamide(reaction with Me₂ AlNR¹² R¹²), an hydroxynitrile (reaction with Me₂AlNH₂ at ca. 80° C.) or an hydroxyester (reaction with R² ONa). Thesebenzylic alcohol derivatives are reacted with the thiol VI as in MethodK to afford LVIII. Alternatively, the lactone LIX can be reacted with VIin the presence of a Lewis acid such as a combination of BF₃ ·Et₂ O andtrifluoroacetic acid to yield LVIII. The groups Q in LVIII can betransformed as described in Methods G, J and K.

METHOD M

The aldehyde LX (represented in compounds III, XI, and XXVI) is reactedwith an organometallic reagent R⁷ CH₂ M and the benzylic alcohol soobtained is oxidized to LXI with an oxidant like activated manganesedioxide. LXI is then reacted with the iodide LXII in the presence of abase such as lithium diisopropylamide to yield the addition productLXIII. Many iodides LXII are known in the art and may be prepared asdescribed for iodides 1 and 2. Reduction with sodium borohydride oraddition of an organometallic reagent affords the benzylic alcohol LXIV,which is then treated as in Method K to give the thioether LXV.

METHOD N

The enolate of the ketone LXVI, obtained by treatment of LXVI with abase such as KH or NaH, is reacted with dimethylcarbonate to yield theketoester LXVII. LXVII is enolized with a base such as NaH and treatedwith the benzylic iodide LXII. The adduct so obtained is thendecarboxylated using conditions such as heating with HCl in acetic acidto afford the ketone LXVIII. In cases where Q² is an ester, a mixture ofketoacid and ketoester is obtained; reesterification of the mixture withdiazomethane or R² I/K₂ CO₃ afford LXVIII. Finally, LXVIII is treated asin Methods M or O to afford LXIX, its isomer or LXVa, allrepresentatives of the structure I.

METHOD O

The hydroxyacid LVI is esterified using conditions such as heating withMeI and K₂ CO₃ or reacting with diazomethane. Treatment of thishydroxyester with an oxidant such as pyridinium chlorochromate oractivated manganese dioxide afford the ketoester LXXI. The ketone isthen reduced using the chiral oxazaborolidine LXXII (see J. Am. Chem.Soc. 1987, 109, 7925-6) in the presence of borane.THF complex.Deprotection of the phenol and reaction with IX as in Method L gave thechiral benzylic alcohol LXXIII. The group Q² of LXXIII can betransformed to a nitrile, an amide or a ketone as described in Method K.The chiral center of LXXIII can be inverted to give LXXIV usingconditions such as: 1) treatment with triphenylphosphine, diethylazodicarboxylate and an acid such as R-(-)α-methoxyphenylacetic acid (achiral acid seems to improve the resolution); and 2) hydrolysis of theester so obtained with a base such as NaOH. Formation of the mesylate,displacement by the thiol VI and transformation of the groups Q as inMethod K yield LXXV and LXXVI, both representatives of the structure I.

METHOD P

Method P is complementary to Method F for the synthesis ofdithioacetals. To the benzaldehyde LX is added one equivalent of each ofthiolacetic acid and the thiol VI in the presence of a Lewis acid suchas BF₃ ·Et₂ O or trifluoroacetic acid. The mixed dithioacetal LXXVIIthus formed is then treated with sodium methoxide in methanol at -20° C.and reacted with a bromide or an iodide to yield LXXVIII, which is ananalog of structure XXX. Transformation of the groups Q can be done asin Method K to afford other derivatives, all of which arerepresentatives of structure I.

METHOD Q

LXXIX is obtained from the addition of vinylmagnesium bromide to thebenzaldehyde LX. LXXIX is then reacted with one equiv of an arylcompound containing a leaving group such as a triflate, an iodide or abromide in the presence of 0.03 equiv. of Pd(OAc)₂, 0.09 equiv oftriphenylphosphine and 1.25 equiv of NaHCO₃ in dimethylformamide at 100°C. to afford LXXX, which is then treated as in Method M or O to affordLXXXI as a chiral compound or as a mixture of isomers.

METHOD R

The benzaldehyde LX is treated as in Method H to afford the styreneLXXXII. The carbamate LXXXIII is then obtained by a Curtiusrearrangement of the acid with diphenylphosphoryl azide andtriethylamine in the presence of an alcohol. Alternatively, the anilinederivative can be formed first by treatment with diphenylphosphorylazide/Et₃ N/H₂ O or with isobutyl chloroformate/NaN₃ /H₂ O. Then,alkylation of the aniline with a chloroformate in the presence of a basesuch as triethylamine affords the carbamate. LXXXIII is finally treatedas in Method D or K of afford LXXXIV.

METHOD S

The compound LVIII in which the group Q² is a sulfone is obtained asfollows. First, a thiophenol is obtained from the allylphenol LXXXV byreaction with sodium hydride and dimethylthiocarbamoyl chloride,rearrangement of the intermediate to the S-dimethylcarbamothioate byheating at reflux in 1,2,4-trichlorobenzene and hydrolysis with sodiummethoxide. Alkylation of the thiophenol give LXXXVI, which is oxidizedto the sulfone with an oxidant such as meta-chloroperbenzoic acid.Ozonolysis of the allyl group afford LXXXVII, which is transformed toLVIII as described in Method K for the conversion of LIV and LVIII.##STR17##

INTERMEDIATES IODIDES Iodide 1 Methyl 2-(iodomethyl)benzoate

Following the procedure in Tetrahedron, 22, 2107, (1966) phthalide wasconverted to 2-(bromomethyl)benzoic acid using HBr in HOAc. The methylester was prepared by well-known methodology.

A mixture of NaI (180 g) and methyl 2-(bromomethyl)benzoate (82.44 g,360 mmol) in acetone (500 mL) was stirred at r.t. for 2 h. The acetonewas evaporated and the product was redissolved in EtOAc. It was washedwith 25% aq. NH₄ OAc followed by 10% aq NaHCO₃, a sodium bisulfitesolution and brine. Evaporation to dryness afforded 100 g (100% yield)of the title iodide.

¹ H NMR (CDCl₃) δ: 3.95 (3H, s), 4.93 (2H, s), 7.32 (1H, m), 7.43 (2H,m), 7.94 (1H, d).

Iodide 2 Methyl 5-chloro-2-(iodomethyl)benzoate Step 16-Chloro-3-hydroxyphthalide

In a 5 L 3-necked round-bottomed flask a solution ofN,N,N'-trimethylethylenediamine (101.6 mL, 0.78 mol) in THF (1 L, driedover 3Å molecular sieves) was cooled to -20° C. Under a nitrogenatmosphere 10.0M n-butyllithium in hexanes (75 mL, 0.75 mol) was addedover 15 min maintaining the temperature at -20° to -25° C. The mixturewas aged at -20° C. for 15 min. A solution of 4-chlorobenzaldehyde (100g, 0.71 mol) in THF (1 L) was added over 20 minutes to the lithium amidemixture maintaining the temperature at -25° to -20° C. The mixture wasaged at -20° C. for 30 minutes. N,N,N', N'-Tetramethylethylenediamine(118 mL, 0.824 mol) was added, followed by the addition ofn-butyllithium (78.4 mL of 10.0M in hexanes, 0.78 mol) maintaining thetemperature at -25° to -20° C. The mixture was stirred at -20° C. for 2h.

In another 5 L 3-necked flask equipped with a thermometer, mechanicalstirrer, gas inlet tube, and outlet for release of the pressure, asolution of 1,3-dimethylimidazolidinone (100 mL) and THF (1 L) wascooled to -30° C. The slurry of the anion was added via cannula over45-60 min maintaining the temperature between -30° and -20° C.Simultaneously, dry CO₂ was added from a tank at a flow rate sufficientto deliver 15-20 equiv of carbon dioxide (CO₂) over the time of theaddition. The CO₂ addition was continued for 5 min after the addition ofthe aryl lithium mixture was complete. The mixture was stirred at -20°C. for 30-60 min and was quenched with 6 N aqueous HCl (860 mL). Thetemperature was allowed to rise to 5°-10° C. during the addition. Themixture was stirred at this temperature for 30 min. Water (860 mL) wasadded and the product was extracted with isopropyl acetate (1×2 L; 1×1L). The product was extracted from the combined isopropyl acetate layerswith 5% aqueous NaHCO₃ (1×2 L; 2×1 L). The combined aqueous layers wereacidified with 6N aqueous HCl (400 mL). The aqueous layer was extractedwith isopropyl acetate (1×1 L; 3×400 mL). The combined layers werewashed with brine (400 mL) and dried (Na₂ SO₄). The filtered solutionwas concentrated to 1 L, whereupon crystals began to form. Cyclohexane(1 L) was added, and the slurry was concentrated to 800 mL; thisprocedure was repeated once again. To the resultant slurry was addedcyclohexane (500 mL) and the mixture was cooled at 10° C. for 1 h. Thelight-yellow solid was filtered, washed with cold cyclohexane (500 mL),and vacuum dried (117.4 g, 89% yield). An analytical sample of thecompound was obtained by recrystallization from cyclohexane/EtOAc: m.p.135.5°-37° C.

¹ H NMR (CD₃ SOCD₃) δ: 8.3 (br s, 1H), 7.90 (d, J=1.85 Hz), 7.85 (dd,J=1.85 and 7.86 Hz, 1H), 7.71 (d, J=7.86 Hz, 2H), 6.7 (br s, 1H).

Anal. calcd for C₈ H₅ O₃ Cl: C, 52.05; H, 2.73. Found: C, 52.12, H,2.75.

Step 2 6-Chlorophthalide (or 6-chloro-1-(3H)-isobenzofuranone)

To a solution of NaBH₄ (1.9 g) in DMF (10 mL) at 0° C. was addeddropwise a solution of the 3-hydroxyphthalide of Step 1 (9.2 g) in DMF(100 mL). After complete addition, the mixture was stirred at roomtemperature for 1 h. To the reaction mixture was added dropwise 6N HCl(20 mL) over a period of 15 min. A white solid was formed and themixture was heated at 70° C. for 1 h. The mixture was cooled to roomtemperature, diluted with H₂ O (100 mL) and extracted with EtOAc. Theorganic layers were washed with H₂ O (3×100 mL), dried over Na₂ SO₄ andevaporated to dryness to give the title product (8.2 g, 97% yield); m.p.108°-109° C.

Step 3

Using the procedure described for Iodide 1 and the reference therein,6-chlorophthalide was converted to the title compound.

¹ H NMR (CDCl₃) δ: 3.95 (3H, s), 4.89 (2H, s), 7.37 (1H, s), 7.4 (1H, d,J=2 Hz), 7.92 (1H, d, J=2 Hz).

IR (KBr) 1725 cm³¹ 1.

Iodide 3 Methyl 3,4-dichloro-6-(iodomethyl)benzoate

This iodide was obtained using the procedure of Iodide 1, from5,6-dichlorophthalide.

KETOESTERS Ketoester 1 Methyl3-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-oxopropanoate

The ketoester was prepared as in Example 402, Step 2.

Ketoester 2 Methyl3-(3-((7-chloro-2-quinolinyl)-methoxy)phenyl)-3-oxopropanoate

A suspension of 60% NaH in oil (11.2 g, 0.28 mol) was washed with two 50mL portions of hexane. It was then suspended in 58 mL of THF and 19.6 mL(0.23 mol) of dimethyl carbonate. Methanol (3.75 mL, 0.092 mol) was thenadded slowly (CAUTION) and the mixture was heated to a gentle reflux.The ketone described in Example 379, Step 1, (28.8 g, 0.092 mol) insolution in 87 mL of THF was added to the NaH suspension dropwise, over50 min, after which the mixture was refluxed for a further 15 min. Themixture was cooled to 0° C. and carefully quenched with 82 mL of 3MHOAc, followed by 110 mL of brine. The slurry was extracted 4 times withCHCl₃, the organic phase was dried and evaporated. The residue waspurified by flash chromatography on a 100 mm diameter×200 mm heightsilica gel column eluted with 1 L of each 7%, 8%, 9% and 10% EtOAc intoluene. The pooled fractions were evaporated to give a black solidwhich was crystallized twice from toluene:hexane 2:1 to yield 24.3 g(72%) of a beige solid. The NMR data suggest a keto-enol mixture.

¹ H NMR (CDCOCD₃)δ:3.68 (2.4H, s), 3.80 (0.6H, s), 4.12 (1.6H, s), 4.96(2H, br s), 5.86 (0.2H, s), 7.2-7.7 (5H, m), 7.77 (1H, d), 8.05 (2H, m),8.43 (1H, d).

Ketoester 3 Methyl3-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-3-oxopropanoate Step 11-(3-(2-(7-Chloro-2-quinolinyl)ethyl)phenyl)ethanone

To a cooled suspension of the nitrile of Example 3, Step 1 (44 g, 0.15mol) in 300 mL of toluene at -78° C. was added 225 mL of Me₃ Al intoluene slowly via a syringe. During addition of Me₃ Al, the nitrile waspartially dissolved in the solution. The reaction was stirred at -78° C.for 15 min and then warmed up to r.t. After 10 min, the reaction mixturewas heated up to reflux for 16 h. It was then cooled down to r.t., andpoured into a mixture of 600 mL of H₂ O, 150 mL of concentrated HCl andexcess ice. The mixture was stirred at r.t. for 1.5 h and the yellowsolid was collected by filtration, washed with toluene and then with H₂O. The solid was partitioned between EtOAc and a NaK tartrate solution.The organic phase was separated and washed once with brine. Afterremoval of the solvent, the residue was crystallized from EtOAc:hexane4:1 to give 29 g (62%) of the title ketone.

Step 2

Using the procedure described for the formation of the Ketoester 2,Ketoester 3 was obtained from the ketone of Step 1.

QUINOLINES Quinoline 1 2-(Bromomethyl)-6,7-dichloroquinoline Step 16,7-Dichloro-2-methylquinoline

Using the procedure of Leir (J. Org. Chem, 42, 911 (1977)), but startingfrom 3,4-dichloroaniline, there was obtained the title compound.

¹ H NMR (CD₃ COCD₃)δ:2.5 (3H, s), 7.45 (1H, d), 8.14 (1H, s), 8.24 (1H,s), 8.35 (1H, d).

Step 2

Using the same procedure as described for Quinoline 3, Step 2, butstarting with the product of Step 1, there was obtained the titlecompound.

¹ H NMR (CD₃ COCD₃)δ:4.80 (2H, s), 7.75 (1H, d), 8.18 (1H, s), 8.25 (1H,s), 8.4 (1H, d).

Quinoline 2 2-(Chloromethyl)quinoline

This quinoline is commercially available.

Quinoline 3 2-(Bromomethyl)-7-(methylsulfonyl)-quinoline Step 12-Methyl-7-(methylsulfonyl)quinoline

To a suspension of 60% NaH in oil (32.0 g, 0.800 mol) in THF (1 L) wasadded 3-mercaptoaniline (100 g) in THF (200 mL) and the mixture wasstirred at r.t. for 1 h. MeI (140 g) was then added and the reactionmixture was stirred overnight at 60°. The mixture was filtered anddistilled to give a crude methyl thioether, b.p. 80°-100° C./0.5 mm Hg.To the crude thioether in 6N HCl (500 mL) at 100° was added dropwisecrotonaldehyde (35 g) over 30 min. The reaction mixture was cooled,neutralized with NH₄ OH and extracted with ethyl acetate. Flashchromatography of the extract using EtOAc:toluene 15:85 afforded thequinaldine (85% pure, 15% of the 5-isomer).

To this quinaldine (14 g) in CH₂ Cl₂ (200 mL) at 0° C. was added MCPBA(meta-chloroperbenzoic acid) (22 g) in CH₂ Cl₂ (100 mL). After 2 hrs,more MCPBA (5 g) was added. The reaction mixture was stirred 1 hr atr.t., cooled to 0° C. and Ca(OH)₂ (30 g) was added. Thirty min. laterthe mixture was filtered and evaporated. Flash chromatography using30-40% EtOAc/toluene afforded the title sulfone.

¹ H NMR (CD₃ COCD₃) δ: 2.75 (3H, s), 3.25 (3H, s), 7.7 (2H, s), 7.95(1H, dd), 8.15 (1H, d), 8.35 (1H, d), 8.5 (1H, br d).

Step 2

To the sulfone of Step 1 (6.5 g) in CCl₄ (200 mL) was added NBS(N-bromosuccinimide) (6.5 g) and benzoyl peroxide (0.2 g). The reactionmixture was heated for 6 hrs, cooled and evaporated. Flash columnchromatography using 10-20% EtOAc/toluene afforded the title compound.

¹ H NMR (CD₃ COCD₃) δ: 3.4 (3H, s), 4.95 (2H, s), 7.9 (1H, d), 8.1 (1H,dd), 8.3 (1H, d), 8.52 (1H, d), 8.6 (1H, d).

Quinoline 4 2-(Bromomethyl)-6-methoxyquinoline Step 12-(Hydroxymethyl)-6-methoxyquinoline

To 6-methoxy-2-methylquinoline (8.5 g, prepared according to the generalprocedure of Leir, (J. Org. Chem., 42, 911 (1977)) in THF at 0° C. wasadded LDA (lithium diisopropylamide) (50 mmol). The reaction mixture wasstirred 30 min. This solution was added via a cannula to a solution ofN-(phenylsulfonyl)-3-phenyloxaziridine) in THF (30 mL) at 0° C. over 15min. After stirring 15 min at 0° C., pH 7 phosphate buffer was added.The mixture was extracted with EtOAc, dried and evaporated. Flashchromatography using 20-40% EtOAc/toluene afforded the title compound.

¹ H NMR (CD₃ COCD₃) δ: 3.9 (3H, s), 4.65 (1H, br t), 4.80 (2H, br d),7.25 (1H, d), 7.3 (1H, d), 7.55 (1H, dd), 7.9 (1H, d), 8.2 (1H, d).

Step 2

To the alcohol from Step 1 (2.5 g) and CBr₄ (5.6 g) in CH₂ Cl₂ (50 mL)at 0° C. was added a solution of DIPHOS(1,2-bis(diphenylphosphino)ethane) (3.4 g) in CH₂ Cl₂ (20 mL) over 10min. The reaction mixture was stirred 1 hr at r.t. and quenched withhexane (50 mL). The reaction mixture was passed through a pad of SiO₂eluting with 30% EtOAc/hexane. The eluant was evaporated andchromatographed using 20% EtOAc/hexane to afford the title bromide (2.5g).

¹ H NMR (CD₃ COCD₃) δ: 3.9 (3H, s), 4.75 (2H, s), 7.25 (1H, d), 7.35(1H, d), 7.6 (1H, dd), 7.85 (1H, d), 8.2 (1H, d).

STYRENES Styrene 1 Methyl2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-2-propenyl)benzoate

The styrene was prepared as in Example 29, Method B, Step 6.

Styrene 2 Methyl2-(3-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-2-propenyl)benzoate

The styrene was prepared as in Example 36, Step 1.

Styrene 3 Methyl2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-2-propenyl)benzoate

Using the procedures of Example 29, Method B, Steps 1-6,3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (see EP 233,763,Example 24, Step 1) was converted to Styrene 3.

Styrene 4 Methyl2-(3-(3-(2-(7-chloro-2-quinolinyl)cyclopropyl)phenyl)-2-propenyl)benzoate

The aldehyde of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (see EP233,763, Example 24, Step 1) was protected as an acetal by heating it atreflux in benzene for 18 h, using a Dean-Stark apparatus, with 1.2equiv. of ethylene glycol and 0.5 equiv. of p-toluenesulfonic acid.Aqueous work up and extraction with EtOAc gave the pure acetal. Thecyclopropanation was done with 1.9 equiv. of the anion obtained fromtrimethylsulfoxonium iodide and NaH in DMSO (dimethylsulfoxide) asdescribed in J. Am. Chem. Soc., 87, 1353 (1965). Then, the acetal wasdeblocked by heating at reflux in THF:HOAc:H₂ O 6:2:1 for 5 h to yield3-(2-(7-chloro-2-quinolinyl)cyclopropyl)benzaldehyde, which wasconverted to Styrene 4 using the procedure of Example 29, Method B,Steps 1-6.

Styrene 57-Chloro-2-((3-(3-(2-(methylsulfonyl)phenyl)-1-propenyl)phenoxy)methyl)quinolineStep 1 S-(2-(2-Propen-1-yl)phenyl)dimethylcarbamothioate

2-Allylphenol was treated with dimethylthiocarbomoyl chloride and NaH,then heated in 1,2,4-trichlorobenzene at reflux as in Example 8, Steps5-6, to afford the title compound.

Step 2 2-(2-Propen-1-yl)thiophenol

A solution of the product of Step 1 (2.00 g, 9.04 mmol) in MeOH (50 mL)was added to a solution of MeONa (832 mg of Na, 36 mmol) in MeOH (60 mL)containing BHT (2,6-di-tert-butyl-4-methylphenol, 100 mg). The resultingmixture was then heated at 50° C. for 18 h and cooled to r.t. Themixture was poured on cold 10% HCl under N₂ and extracted with Et₂ O.The organic phase was dried over Na₂ SO₄, filtered and evaporated atreduced pressure. The desired compound was purified by flashchromatography on silicic acid with hexane to provide 1.00 g (75%) ofthe title compound as a colorless oil.

¹ H NMR (CD₃ COCD₃) δ: 3.42 (2H, d), 4.08 (1H, s), 5.05 (2H, m), 5.93(1H, m), 7.00-7.41 (4H, m).

Step 3 1-(Methylthio)-2-(2-propen-1-yl)benzene

To a solution of the thiol of Step 2 (1.00 g, 6.71 mmol) in DMF (22 mL)containing BHT (10 mg) and MeI (209 mg, 8.72 mmol) at 0° C. was addedNaH (20.9 mg, 8.7 mmol). After 1 h at r.t., the reaction mixture wasquenched by the addition of 25% aq NH₄ OAc and extracted with EtOAc inthe usual manner. The title thioether was isolated (770 mg, 80%) byflash chromatography on silica with hexane.

¹ H NMR (CD₃ COCD₃) δ: 2.41 (3H, s), 3.41 (2H, d), 5.01 (2H, m), 5.95(1H, m), 6.95-7.33 (4H, m).

Step 4 1-(Methylsulfonyl)-2-(2-propen-1-yl)benzene

To a solution of the thioether of Step 3 (110 mg, 0.674 mmol) in MeOH(2.2 mL) at 0° C. was added a suspension of oxone (1.24 g, 2.01 mmol) inH₂ O. After 0.5 h at r.t., water was added until obtention of ahomogenous solution. After a few minutes, the desired product wasextracted with EtOAc, dried over Na₂ SO₄, filtered and evaporated. Thetitle compound was purified by flash chromatography to give 56 mg (42%)of material.

¹ H NMR (CD₃ COCD₃) δ: 3.16 (3H, s), 3.91 (2H, d), 5.12 (2H, m), 6.08(1H, m), 7.50 (2H, m), 7.66 (1H, m), 8.01 (1H, m).

Step 5

2-(Methylsulfonyl)phenylacetaldehyde was obtained from the ozonolysis(Example 366, Step 2) of the sulfone of Step 4. It was then transformedto the title styrene using the procedures of Example 29, Method B, Step4.

Styrene 6 Ethyl((2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-2-propenyl)phenyl)amino)carboxylate

Using the procedure of Example 29, Method A, Step 3, the styrene 1 washydrolyzed to the acid, which was then transformed to the titlecarbamate as in Example 178, Step 1.

Styrene 7 Ethyl((2-(3-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-2-propenyl)phenyl)amino)carboxylate

This styrene was obtained from Styrene 2 as described for Styrene 6.

Styrene 87-Chloro-2-(2-(3-(3-(2-(((trifluoromethyl)sulfonyl)amino)phenyl)-1-propenyl)phenyl)ethyl)quinolineStep 1 2-(3-(2-(7-Chloro-2-quinolinyl)ethyl)-2-propenyl)aniline

Using the procedure of Example 29, Method A, Step 3, Styrene 2 washydrolyzed to the acid. This acid (1.65 g, 3.9 mmol), triethylamine (1.1mL, 7.7 mmol) and diphenylphosphoryl azide (1.7 g, 6.2 mmol) were mixedtogether in dioxane (75 mL) and the solution was stirred 2 h at r.t.followed by 10 min. at 60° C. Water (2 mL) was added and the mixture washeated at 90° C. for 2 h. Evaporation of the solvent gave a crude oilwhich was subjected to flash chromatography (EtOAc:Hexane:Toluene) togive the desired product (875 mg).

Step 2

The product of Step 1 (415 mg, 1.0 mmol) was dissolved in CH₂ Cl₂ (40mL) containing triethylamine (304 μL, 2.2 mmol) at -78° C.Trifluoromethanesulfonic anhydride (193 μL, 1.1 mmol) was added dropwiseand the reaction mixture was stirred 3 h with slow warming to 0° C.followed by an additional 2 h at this temperature. Water (15 mL) wasadded, the organic phase was decanted and the aqueous one was extractedwith EtOAc and CH₂ Cl₂. The combined organic extracts were washed withbrine, dried over MgSO₄, and evaporated in vacuo. Flash chromatographyof the residue (10% to 30% EtOAc in hexane with 0.05% of formic acid)gave the title product (370 mg) along with somebis(trifluoromethylsulfonamide) (136 mg) which could be hydrolyzed tothe desired mono trifluoromethylsulfonamide with aqueous KOH in amixture of MeOH and THF.

Styrene 91-((2-(3-(3-(2-(7-Chloro-2-quinolinyl)ethyl)phenyl)-2-propenyl)phenyl)amino)2,2-dimethyl-1-propanone

Using the procedure of Example 381, but using trimethylacetyl chlorideinstead of acetyl chloride, the aniline precursor of Styrene 8 (Step 1)was transformed to the title styrene.

THIOLS Thiol 1 Methyl 3-mercaptopropanoate

The thiol is commercially available.

Thiol 2 3-Mercaptopropanoic acid

The thiol is commercially available.

Thiol 3 N,N-Dimethyl 3-mercaptopropanamide

The thiol was prepared as in U.S. Pat. No. 4,851,409, Example 27, Step4.

Thiol 4 Ethyl 3-mercapto-2-methylpropanoate

The thiol was prepared as in Example 372, Step 1.

Thiol 5 3-Mercapto-2-methylpropanoic acid

The thiol was prepared as in Example 372, Step 1.

Thiol 6 Ethyl 2-ethyl-3-mercaptopropanoate

The thiol was prepared as in Example 113, Step 2.

Thiol 7 2,2-Dimethyl-3-mercaptopropanoic acid

Using the procedure described in Chem. Abstr., 58, 11490b, c, (1963)this thiol was obtained from 3-bromo-2,2-dimethylpropanoic acid (J. Am.Chem. Soc. 3016 (1955)) by substitution of the bromide by KSH.

Thiol 8 2,2-Diethyl-3-mercaptopropanoic acid

Using the procedure described for Thiol 7 and the references therein,2-ethylbutyraldehyde was converted to the title thiol.

Thiol 9 Ethyl 1-(mercaptomethyl)cyclopropanecarboxylate Step 11,1-Cyclopropanedimethanol

To a suspension of LiAlH₄ (15.0 g, 395 mmol) in THF (500 mL) at 0° C.was added dropwise, to maintain the temperature below 55° C., a solutionof diethyl 1,1-cyclopropanedicarboxylate (50.0 g, 268 mmol) in THF (250mL). When the reaction was completed, H₂ O (15 mL), 15% NaOH (15 mL) andH₂ O (45 mL) were added successively. The mixture was then filtered oncelite and washed with THF. The filtrate was evaporated to dryness andthe resulting oil was distilled at 110° C./5 mm Hg to give 17.7 g (66%)of the title diol.

¹ H NMR (CDCl₃) δ: 0.41 (4H, s), 2.30 (2H, t), 2.58 (4H, d).

Step 2 Methyl 1-(bromomethyl)cyclopropanecarboxylate

The diol of Step 1 was oxidized with KMnO₄ (as described in Chem. Ber.,2254 (1973)) to give 1-(hydroxymethyl)cyclopropanecarboxylic acid, whichwas esterified with diazomethane. Using CBr₄ /DIPHOS (Example 29, MethodB, Step 2), the alcohol was converted to the title bromide.

Step 3

To a solution of the bromide of Step 2 (460 mg, 2.39 mmol) in EtOH:H₂ O3:1 (5.5 mL) at 0° C. were added, under a flow of nitrogen, K₂ CO₃ (182mg) and NaSH (282 mg, 5.03 mmol). After 10 h at r.t., the reaction wasquenched by the addition of 10% HCl and the resulting mixture wasextracted with EtOAc, dried with Na₂ SO₄ and evaporated. The thiol waspurified by flash chromatography (20% EtOAc/Hexane) to give 150 mg (43%)of the title compound.

¹ H NMR (CD₃ COCD₃) δ: 0.88 (2H, m), 1.16 (2H, m), 2.70 (2H, d), 3.58(3H, s).

Thiol 10 Ethyl 4-mercaptobutanoate

The thiol was prepared as in Chem. Abstr., 58, 11490b, c (1963).

Thiol 11 Methyl 4-mercapto-2-methylbutanoate

Using the procedure described in Chem. Abstr., 58, 11490b, c (1963) thisthiol was obtained from methyl 4-bromo-2-methylbutanoate (Helv. Chem.Acta, 63, 2508 (1980)).

Thiol 12 Ethyl 3-mercapto-2-propylpropanoate

Starting from diethyl 2-propylpropanedioate and following the procedureof Arch. Pharm., 313, 846 (1980) and Example 113, Steps 1 and 2, thetitle compound was prepared.

Thiol 13 2-Ethyl-3-mercaptopropanoic acid

Hydrolysis of Thiol 6 as in Example 1, Step 8 gave the title compound.

Thiol 14 Ethyl alpha-(mercaptomethyl)-cyclopropaneacetate Step 1Cyclopropaneacetonitrile

A solution of 16.7 g (0.34 mol) of NaCN in 200 mL of DMSO was heated to70° C., and 40 g (0.296 mol) of (bromomethyl)cyclopropane were added.After 2 h at this temperature, a heavy solid stopped the stirring. Themixture was cooled to r.t. and the solid was loosened with water. Themixture was partitioned between 1 L of water and 400 mL of Et₂ O, andthe aqueous layer was reextracted twice with Et₂ O. The combined organicphases were dried over MgSO₄ and evaporated. Distillation afforded 20.75g (87%) of the title compound as a colorless liquid; b.p. 34.5°-36.5°C./15 mm Hg.

¹ H NMR (CDCl₃) δ: 0.34 (2H, m), 0.67 (2H, m), 1.1 (1H, m), 2.38 (2H,d).

Step 2 Ethyl alpha-cyanocyclopropaneacetate

To a suspension of 13 g (0.54 mol) of NaH in 150 mL of THF was added 76mL (0.625 mol) of diethylcarbonate. This mixture was heated to gentlereflux, and 0.5 mL (9 mmol) of ethanol was added carefully. This wasfollowed by the addition of a solution of 14.6 g of the nitrile fromStep 1 in 40 mL of THF, over a period of 2 h. After addition, themixture was refluxed an additional 45 min before cooling in ice. Carefuladdition of 200 mL of 3M HOAc, followed by 250 mL of brine loosened anysolid. This mixture was extracted twice with CH₂ Cl₂, the organic phasewas dried over Na₂ SO₄ and evaporated. Distillation afforded 21.26 g(77%) of the title compound as a colorless oil; b.p. 57° C./0.2 mm Hg.

¹ H NMR (CDCl₃) δ: 0.57 (2H, m) 0.77 (2H, m), 1.35 (4H, m), 3.24 (1H,d), 4.28 (2H, q)

Step 3 Diethyl cyclopropylpropanedioate

At 10° C., 100 mL of EtOH was saturated with gaseous HCl. A solution of25.03 g (0.164 mol) of the cyanoester from Step 2 in 100 mL of EtOH wasthen added, and this solution was heated to 60° C. in a rubber septumstoppered flask for 15 h. The mixture was then poured onto 600 mL of iceand stirred until it reached r.t. Ether extraction, Na₂ SO₄ drying andevaporation afforded an oil which was distilled to give a 28.7 g (88%)of the title compound as a colorless oil; b.p. 55° C./0.05 mm Hg.

¹ H NMR (CDCl₃) δ: 0.33 (2H, br q), 0.68 (2H, br q), 1.30 (6H, t), 1.35(1H, m), 2.61 (1H, d), 4.24 (4H, q).

Step 4 Ethyl 2-cyclopropyl-2-propenoate

Using the procedure described in Arch. Pharm. 313, 846 (1980), the titlecompound was obtained from the malonate of Step 3.

Step 5 Ethyl alpha-((acetylthio)methyl) cyclopropaneacetate

A solution of 14.1 g (0.100 mol) of the acrylate from Step 4 in 57 mL(0.40 mol) of triethylamine was diluted with 21.5 mL (0.30 mol) ofthiolacetic acid. This solution was heated at 70° C. for 8 h and left atr.t. for 15 h. Addition of a volume of Et₂ O gave two phases, which wereseparated. The bottom phase was reextracted with Et₂ O. The organicphases were washed twice with 25% aq NH₄ OAc, once with 10% aq NH₄ OAC,dried over MgSO₄ and evaporated. Kugelrohr distillation at 120° C./0.25mm Hg gave 14.89 g (69%) of the title compound as an orange oil.

¹ H NMR (CDCl₃) δ: 0.38 (2H, m), 0.57 (2H, m), 0.96 (1H, m), 1.28 (3H,t), 1.85 (1H, m), 2.33 (3H, s), 3.21 (2H, m), 4.18 (2H, m).

Step 6

Hydrolysis of the thioester of Step 5 using the procedure of Example113, Step 2, afforded the title thiol.

Thiol 15 Methyl 3-mercapto-2-hydroxy-2-methylpropanoate Step 1 Ethyl2-methyl-2-oxiranecarboxylate

To a solution of 85% m-CPBA (meta-chloroperbenzoic acid, 42.0 g, 244mmol) in 1,2-dichloroethane (500 mL) containing BHT (500 mg) was addedin one portion ethyl methacrylate (10 g, 174 mmol). After 2 h at 70° C.,the reaction mixture was filtered and the solid washed with CH₂ Cl₂. Thefiltrate was then partially evaporated and diluted with CH₂ Cl₂. Theorganic phase was successively washed with sat. NaHCO₃, aq KI, Na₂ S₂ O₃and NaHCO₃. The organic phase was then dried over Na₂ SO₄, filtered andevaporated. The desired epoxide was distilled at 72° C./16 mm Hg to give16.0 g (70%) of title material.

¹ H NMR (CD₃ COCD₃) δ: 1.35 (3H, t), 1.61 (3H, s), 2.91 (1H, d), 3.16(1H, d), 4.33 (2H, q).

Step 2 Ethyl 3-(benzylthio)-2-hydroxy-2-methylpropanoate

To a solution of the epoxide of Step 1 (5.0 g, 38 mmol), in EtOH (22 mL)at 0° C. was added an EtOH solution containing NaOH (1.55 g) and benzylmercaptan (4.2 g, 38 mmol). After 1 h, the reaction mixture was quenchedby the addition of 25% aq NH₄ OAc and the thioether extracted withEtOAc. After drying over NaSO₄, evaporation and flask chromatography,8.8 g (70%) of title material were obtained.

¹ H NMR (CD₃ COCD₃) δ: 1.25 (3H, t), 1.38 (3H, s), 2.70 (2H, AB), 3.41(1H, s), 3.58 (2H, AB), 4.15 (2H, q), 7.13-7.33 (5H, m).

Step 3

Using the procedure of Example 229, Steps 3-5, the compound of Step 2was converted to the title thiol.

Thiol 16 2-(Mercaptomethyl)benzoic acid

2-(iodomethyl)benzoic acid, a precursor of Iodide 1, was substitutedwith thiolacetic acid (1.2 equiv) in the presence of K₂ CO₃ in DMF at60° C. for an hour to give the thioacetate, which was hydrolyzed withNaOH to give the title thiol.

Thiol 17 5-Chloro-2-(mercaptomethyl)benzoic acid

This thiol was obtained from Iodide 2 as described for Thiol 16.

Thiol 18 Methyl 3-mercapto-2-methoxypropanoate

The thiol was obtained as in Example 229, Step 5.

The invention is further defined by reference to the following examples,which are intended to be illustrative and not limiting.

All temperatures are in degrees Celsius.

EXAMPLE 12-(3-(3-(2-(7-chloroquinolin-2-yl)ethyl)phenyl)-3-(2-carboxyethylthio)propyl)benzoicacid, disodium salt Step 1 Preparation of(3-cyanophenylmethyl)triphenylphosphonium bromide

To a solution of 3-bromomethylbenzonitrile (19.6 g) in CH₃ CN (500 ml)triphenylphosphine (Ph₃ P) was added (30 g). The reaction mixture wasstirred at 60° cooled and filtered. The title product thus obtained wasdried and used as such for the next step.

Step 2 Preparation of 2-(1-(3-cyanophenyl)propen-3-yl)benzyl alcohol

To phosphonium salt (step 1) (13.4 g) in tetrahydrofuran (THF) (100 mL)at -78° was added potassium hexamethyldisilazide (KHMDS) (0.6M intoluene) (50 mL). The reaction mixture was warmed to 0° for 1 hr. Aftercooling to -78°, 1H-3-hydroxy-3,4-dihydrobenzo(c)pyran (2 g) in THF (10mL) was added. The mixture was warmed to room temperature (RT) for 1 hr,poured onto pH 7 buffer, extracted with ethyl acetate, dried andevaporated. Flash chromatography using 20% ethyl acetate in tolueneafforded the title compound.

p.m.r. (CDCl₃) δ (ppm): 1.8 (m, 1H), 3.7 (m, 2H), 5.64 (d, 1H), 5.84 (d,1H), 5.9-6.6 (m, 2H), 7.1-7.7 (m, 8H).

Step 3 Preparation of 2-(1-(3-cyanophenyl)propen-3-yl))benzaldehyde

To a suspension of pyridinium chlorochromate (PCC) (10 g) and 4Apowdered molecular sieves in CH₂ Cl₂ (200 mL) was added the alcohol fromstep 2. The mixture was stirred 1 hr at room temperature, ether wasadded and the mixture was filtered through a pad of SiO₂ using 30% ethylacetate-hexane as eluant. The filtrate was evaporated to afford thetitle compound which was used as such for the next step.

Step 4 Preparation of methyl-2-(1-(3-cyanophenyl)propen-3-yl)benzoate

To a solution of aldehyde (step 3) in MeOH (200 mL), AcOH (1.2 mL) andNaCN (4 g) was added MnO₂ (20 g). The mixture was stirred for 2 hrs andpoured onto H₂ O (1 L). The aqueous phase was extracted with ethylacetate (2×500 mL) and the combined organic phases were dried andevaporated. Flash chromatography of the residue using 5% ethyl acetatein toluene afforded the title compound as a mixture of cis and transisomers.

p.m.r. (CDCl₃) δ (ppm): 3.4 and 3.6 (s, 3H), 3.7 and 3.9 (dd, 2H),6.2-6.8 (m, 2H), 7.4-7.8 (m, 7H), 8.1 (m, 1H).

Step 5 Preparation of methyl2-(3-(2-(methoxycarbonyl)ethylthio)-3-(3-cyanophenyl)propyl)benzoate

To a solution of olefin (step 4) (367 mg) in CH₂ Cl₂ (10 mL) was addedmethyl 3-mercaptopropionate (200 mg) and AlCl₃ (0.7 g). The mixture wasstirred for 3 hrs. at room temperature, quenched with 25% aq. NH₄ OAcand extracted with ethyl acetate. The organic phase was dried andevaporated. Flash chromatography of the residue using 10% ethyl acetatein toluene afforded the title compound.

p.m.r. (CDCl₃) δ (ppm): 2.0-2.3 (m, 2H), 2.4-2.7 (m, 4H), 2.8-3.1 (m,2H), 3.7 (s, 3H), 3.9 (s, 3H), 3.9 (t, 1H), 7.1-7.7 (m, 7H), 7.9 (d,1H).

Step 6 Preparation of methyl2-(3-(2-(methoxycarbonyl)ethylthio)-3-(3-formylphenyl)propyl)benzoate

HCl (gas) was bubbled into a suspension of SnCl₂ (1.2 g) in ether until2 layers were formed. The cyano compound (350 mg) (step 5) was thenadded. The mixture was stirred 3 hours at room temperature and carefullyquenched with H₂ O at 0°. The reaction mixture was poured onto pH 7buffer (300 mL), extracted with ethyl acetate (200 mL), and the organicphase was dried and evaporated. Flash chromatography of the residueusing 25% ethyl acetate in hexane afforded the title compound.

p.m.r. (CDCl₃) δ (ppm): 2.2-2.3 (m, 2H), 2.5-2.7 (m, 4H), 2.85-3.2 (m,2H), 3.75 (s, 3H), 3.95 (s, 3H), 4.0 (s, 1H), 7.2-8.0 (m, 8H), 10.1 (2,1H).

Step 7 Preparation of methyl2-(3-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(methoxycarbonyl)ethylthio)propyl)benzoate

To a suspension of ((7-chloroquinolin-2-yl)methyl)triphenylphosphoniumbromide (EP 233,763, Example 4, step 2) (489 mg) in THF (5 ml) at -78°was added butyllithium (0.51 ml of 1.6N). The reaction mixture wasstirred at -78° 1 hr and aldehyde (350 mg) (step 6) in THF (2 ml) wasadded. The mixture was warmed to RT, poured onto buffer (pH 7),extracted with ethyl acetate, and the organic phase was dried andevaporated. Flash chromatography using 25% ethyl acetate/hexane affordedthe title compound.

p.m.r. (CD₃ COCD₃) δ (ppm): 2.3-2.4 (m, 2H), 2.5-2.7 (m, 4H), 2.85-3.15(m, 2H), 3.65 (s, 3H), 3.85 (s, 3H), 4.05 (t, 1H), 7.3-8.0 (m, 13H),8.05 (d, 1H), 8.3 (d, 1H).

Step 8

To the diester (step 7) in THF (5 mL) and MeOH (5 mL) was added LiOH (5mL of 1N). The solution was stirred 3 days at RT, partitioned betweenEtOAc/H₂ O (acidified with AcOH), and the organic phase was dried andevaporated to give the diacid. To the diacid was added 2 eq. of NaOH andthe solution was freeze dried to give the title compound.

Anal. Calcd. for C₃₀ H₂₄ NO₄ SNa₂ Cl·3H₂ O: C 57.18; H 4.79; N 2.22; Na7.28. Found: C 57.70; H 4.63; N 2.13; Na 7.52.

EXAMPLE 22-(3-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(dimethylcarbamoyl)ethylthio)propyl)benzoicacid, sodium salt

Using the procedure of Example 1 but replacing methyl3-mercaptopropionate with 3-mercapto-N,N-dimethylpropionamide in step 5and using 1 eq. of NaOH in step 8 instead of 2 eq. NaOH there wasobtained the title compound.

p.m.r. (CD₃ COCD₃) δ (ppm): 2.2-2.3 (m, 2H), 2.4-2.7 (m, 4H), 2.8 (s,3H), 2.9 (s, 3H), 2.85-3.2 (m, 2H), 4.05 (t, 1H), 7.0-8.0 (m, 13H), 8.0(d, 1H), 8.3 (d, 1H).

EXAMPLE 33-(3-(2-(7-chloroquinolin-2-yl)ethyl)phenyl)-(2-(dimethylcarbamoyl)ethylthio)methyl)benzoicacid, sodium salt Step 1 Preparation of3-(2-(7-chloroquinolin-2-yl)ethyl)benzonitrile

To 7-chloroquinaldine (18 g) in THF (200 mL) at -78° was added lithiumdiisopropylamide (LDA) (0.1M). The reaction mixture was stirred for 30min at -78° and added dropwise to a solution of3-(bromomethyl)benzonitrile (19.6 g) in THF (200 mL) at 0°. The mixturewas stirred 2 hrs at 0°, quenched with 25% aq. NH₄ OAc, extracted withethyl acetate (500 mL) and the organic phase was dried and evaporated.Flash chromatography using 20% ethyl acetate/hexane afforded the titlecompound.

p.m.r. (CDCl₃) δ (ppm): 3.3-3.4 (m, 4H), 7.0-8.2 (m, 9H).

Step 2 Preparation of 3-(2-(7-chloquinolin-2-yl)ethyl)benzaldehyde

To a solution of nitrile (step 1) (10 g) in formic acid (150 mL) and H₂O (50 mL) was added Ni-Al alloy (6 g). The reaction mixture was heatedat 130° for 2 days, filtered and evaporated. The residue was partitionedbetween ethyl acetate (500 mL) and aqueous NaHCO₃, and the organic phasewas dried and evaporated. Flash chromatography using 25% ethyl acetatehexane afforded the title aldehyde which was used as such for the nextstep.

Step 3 Preparation of3-((3-(2-(7-chloroquinolin-2-yl)ethyl)phenyl)hydroxymethyl)benzoic acid

To a solution of 3-bromobenzoic acid (0.8 g) at -100° in THF (20 mL) wasadded dropwise 2 eq. of n-butyllithium in hexane. The mixture was warmedto -78° and aldehyde (1 g) (step 2) in THF (5 mL) was added dropwiseover 15 min. After stirring 2 hrs at -78° the reaction mixture wasquenched with buffer (25% aq. NH₄ OAc), extracted with ethyl acetate,and the organic phase was dried and evaporated. Flash chromatography ofthe residue using 15% to 25% acetone/toluene/acetic acid 0.1% affordedthe title compound.

p.m.r. (CDCl₃) δ (ppm): 3.1 (m, 2H), 3.3 (m, 2H), 5.8 (s, 1H), 6.0-7.0(bs, 1H), 7.05-7.60 (m, 8H), 7.70 (d, 1H), 8.0 (m, 2H), 8.1-8.2 (m, 2H).

Step 4

To a solution of alcohol (step 3) (0.4 g) in CH₂ Cl₂ (25 mL) was added3-mercapto-N,N-dimethylpropionamide (0.2 mL) and AlCl₃ (800 mg). Thereaction mixture was stirred 1 hr at RT, and quenched with 25% NH₄ OAc(100 mL)/AcOH (2 mL)/THF (50 mL) and EtOAc (200 mL). The organic phasewas separated dried and evaporated. Flash chromatography of the residueusing 25% to 40% acetone/toluene/acetic acid (0.1%) afforded the acid ofthe title compound.

p.m.r. (CD₃ COCD₃) δ (ppm): 2.2-2.4 (m, 4H), 2.55 (s, 3H), 2.65 (s, 3H),2.8-3.0 (m, 4H), 5.15 (s, 1H), 7.0-8.0 (m, 13H).

Step 5

The acid was treated with NaOH (1 eq.) in H₂ O/EtOH, evaporated andfreeze dried to give the title compound.

Anal. Calcd. for C₃₀ H₂₈ N₂ SO₃ ClNa·H₂ O: C 62.75; H 5.45; N 4.86; Na4.00. Found: C 62.35; H 5.38; N 5.30; Na 3.53.

EXAMPLE 45-((3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)(2-(dimethylcarbamoyl)ethylthio)methyl)thiophene-2-carboxylicacid Step 1 Preparation of5-((3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)hydroxymethyl)thiophene-2-carboxylicacid

At -78° C., Buli, 1.6M in hexanes (7.5 mL, 2.3 equiv.) was addeddropwise to a solution of thiophene-2-carboxylic acid (0.784 g, 1.2equiv.) in THF (20 mL) and the mixture was stirred at -78° C. for 30minutes. Then a solution of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (EP 233,763, Example 24, step 1) (1.515 g, 5.15 mmoles) inTHF (25 mL) was added dropwise. Stirring was continued for an hour at-78° C. and the reaction was quenched with 25% aqueous NH₄ OAc. Themixture was acidified to pH 5 with acetic acid and extracted with EtOAc.The organic fraction was dried over Na₂ SO₄ and evaporated. Flashchromatography on silica using EtOAc:toluene:AcOH 30:70:1 and 40:60:1yielded the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 6.80 (s, 1H), 7.32-7.65 (m, 6H), 7.70 (d,1H), 7.82-8.04 (m, 5H), 8.33 (d, 1H).

Step 2

At -10° C., AlCl₃ (2.323 g, 8 equiv.) was added to a solution of thehydroxyacid of step 1 (915 mg, 2.17 mmoles) and3-mercapto-N,N-dimethylpropionamide (587 mg, 2 equiv.) in CH₂ Cl₂ (45mL) and the mixture was stirred at 0° C. for 1.5 hours. An oilseparated, which was collected with a spatula and quenched with THF: 25%aqueous NH₄ OAc ˜1:1. The remaining reaction mixture was stirred 30minutes at room temperature and quenched at 0° C. with 25% aqueous NH₄OAc. The solutions were combined, acidified with acetic acid andextracted with EtOAc. Drying the organic phase over Na₂ SO₄ and flashchromatography of the residue using acetone:toluene:AcOH 20:80:1 and30:70:1 afforded the title acid.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.60 (m, 2H), 2.70 (m, 2H), 2.84 (s, 3H),2.96 (s, 3H), 6.60 (s, 1H), 7.37-7.58 (m, 5H), 7.63 (d, 1H), 7.77 (d,1H), 7.82-8.03 (m, 5H), 8.33 (d, 1H).

EXAMPLE 5 3-((3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)(2-(dimethylcarbamoyl)ethylthio)methyl)benzoic acid Step 1 Preparationof 3-((3-(3-(7-chloroquinolin-2-yl)ethenyl)phenyl)hydroxymethyl)benzoicacid

To the dilithium salt (5.92 mmoles) obtained from 3-bromobenzoic acid(W. E. Parham and Y. A. Sayed, J. Org. Chem., 39, 2051 (1974)), asolution of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (1.503 g,5.16 mmoles) in THF (25 mL) was added dropwise at -78° C. The mixturewas stirred 2 hours at -78° C. and was quenched with 25% aqueous NH₄OAc. The mixture was acidified to pH 5 with AcOH and extracted withEtOAc. The organic fractions were dried over Na₂ SO₄ and evaporated.Flash chromatography on silica using EtOAc:toluene:AcOH 30:70:1 yieldedthe title compound.

¹ H NMR (CD₃ COCD₃ ·DMSO-d6) δ (ppm): 5.90 (s, 1H), 6.00 (s, 1H, OH),7.36-7.58 (m, 5H), 7.62 (d, 1H), 7.73 (d, 1H), 7.82-8.02 (m, 6H), 8.13(s, 1H), 8.37 (d, 1H).

Step 2

At 0° C., AlCl₃ (1.182 g, 7.5 equiv.) was added to a suspension of thehydroxyacid of step 1 (492 mg, 1.183 mmoles) and3-mercapto-N,N-dimethylpropionamide (327 mg, 2 equiv.) in CH₂ Cl₂ (12mL). The mixture was stirred at 0° C. for 1.5 hours and was quenchedwith THF:25% aqueous NH₄ OAc. Acidification to pH 5 with AcOH,extraction with EtOAc, drying the organic phase over Na₂ SO₄ and flashchromatography on silica using acetone:toluene:AcOH 20:80:1 afforded thetitle acid.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.63 (m, 2H), 2.73 (m, 2H), 2.83 (s, 3H),2.95 (s, 3H), 5.62 (s, 1H), 7.40-7.56 (m, 5H), 7.65 (d, 1H), 7.79-8.03(m, 7H), 8.22 (s, 1H), 8.34 (d, 1H).

EXAMPLE 64-((3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)(2-(dimethylcarbamoyl)ethylthio)methyl)benzoicacid

Using the same procedure as for Example 5, but substituting3-bromobenzoic acid by 4-bromobenzoic acid in step 1, the title compoundwas prepared.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.62 (m, 2H), 2.72 (m, 2H), 2.84 (s, 3H),2.95 (s, 3H), 5.59 (s, 1H), 7.38-7.57 (m, 4H), 7.60-7.73 (m, 3H),7.82-8.07 (m, 7H), 8.33 (d, 1H).

EXAMPLE 73((2-carboxyethylthio)(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)methyl)benzoicacid

To a suspension of the hydroxyacid of Example 5, step 1, (193 mg, 464μmoles) in CH₂ Cl₂ (5 mL), 3-mercaptopropionic acid (45 μL, 1.1 equiv.)was added, followed by AlCl₃ (254 mg, 4 equiv.) and2,6-di-tert-butyl-4-methylphenol (23 mg, 0.2 equiv.). The reactionmixture was stirred at room temperature 6.7 hours. Then, at 0° C., THFwas added, followed by 25% aqueous NH₄ OAc. The mixture was acidified topH 5 with AcOH and was extracted with EtOAc. Drying of the organic phaseover Na₂ SO₄ and flash chromatography of the residue on silica usingacetone:toluene:AcOH 10:90:1 afforded the title diacid.

¹ H NMR (CD₃ COCD₃ ·DMSO) δ (ppm): 2.57 (m, 2H), 2.69 (m, 2H), 5.62 (s,1H), 7.40-7.58 (m, 5H), 7.66 (d, 1H), 7.81 (d, 1H), 7.85-8.04 (m, 6H),8.20 (s, 1H), 8.35 (d, 1H).

EXAMPLE 86-(3-carboxyphenylthio)-6-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-methylhexanoicacid Step 1 Preparation of methyl3-methyl-5-(methylsulfonyloxy)pentanoate

To methyl 5-hydroxy-3-methylpentanoate (B. Lythgoe, J. Chem. Soc.,Perkin Trans. I, 834 (1978)) (9.63 g, 65.9 mmoles) in 200 mL CH₂ Cl₂ at-78° C., Et₃ N (14 mL, 1.5 equiv.) and methanesulfonyl chloride (5.6 mL,1.1 equiv.) were added. After one hour of stirring at room temperature,25% NH₄ OAc was added. Extraction with CH₂ Cl₂, filtration of theorganic phase through silica and evaporation afforded the titlecompound, which was used as such in the next step.

Step 2 Preparation of methyl 5-iodo-3-methylpentanoate

The mesylate (step 1, 14.4 g, 6.42 mmoles) and NaI (48 g, 5 equiv.) wereheated to reflux in 200 mL acetone for 3 hours. The mixture was thenfiltered through celite and the solvent evaporated. The residue waspartionned between water and Et₂ O, the ether extract washed with 5% Na₂S₂ O₃ and brine, dried and evaporated. Flash chromatography of theresidue on silica with EtOAc:hexane 2.5:97.5 afforded the titlecompound.

¹ H NMR (90 MHz, CDCl₃) δ (ppm): 1.00 (d, 3H), 1.70-2.43 (m, 5H), 3.20(t, 2H), 3.67 (s, 3H).

Step 3 Preparation of(5-methoxy-3-methyl-5-oxopentyl)triphenylphosphonium iodide

Triphenylphosphine (14.6 g, 2 equiv.) and the iodide (step 2, 7.85 g,27.6 mmoles) were heated to 80° C. in 50 mL of toluene for 24 hours andat 100° C. 6 hours. The mixture was allowed to cool to room temperature,the toluene layer was discarded and the remaining oil heated in toluenefor another hour. After cooling to room temperature, the toluene layerwas removed. The remaining oil was heated for one hour in ether, theether was removed at room temperature and the remaining oil dried undervacuum.

¹ H NMR (CDCl₃) δ (ppm): 1.09 (d, 3H), 1.50-2.00 (m, 3H), 2.26-2.45 (m,2H), 3.59 (s, 3H), 3.50-3.85 (m, 2H), 7.69-7.90 (m, 15H).

Step 4 Preparation of methyl 6-(3-cyanophenyl)-3-methyl-5-hexenoate

Under a continuous flow of N₂ at -78° C., KHMDS (0.684M in toluene, 110mL, 1.3 equiv.) was added dropwise to a solution of the phosphonium salt(step 3, 0.133M in THF:HMPA 10:1, 620 mL, 1.4 equiv.) and3-cyanobenzaldehyde (7.702 g, 58.7 mmoles) over a period of 30 minutes.The mixture was then allowed to warm to room temperature and was stirredfor a further 2 hours. 25% aqueous NH₄ OAc was added and the aqueouslayer was extracted with EtOAc. The organic layer was washed twice withbrine, dried over Na₂ SO₄ and evaporated. The residue was purified byflash chromatography on silica using EtOAc:hexane 7.5:92.5 and 10:90 toafford the title product.

¹ H NMR (CDCl₃) δ0.98 (d, 3H), 2.07-2.42 (m, 5H), 3.66 (s, 3H), 5.79(td, 1H), 6.48 (d, 1H), 7.40-7.59 (m, 4H) p.p.m.

Step 5 Preparation ofO-(3-(methoxycarbonyl)phenyl)dimethylcarbamothioate

At 0° C., NaH (59.6% in oil, 2.975 g, 1.1 equiv.) was added portionwiseto a solution of methyl 3-hydroxybenzoate (10.22 g, 67.2 mmoles) indimethylformamide (70 mL) and the mixture was stirred 30 minutes at roomtemperature. Then, dimethylthiocarbamoyl chloride (11.95 g, 1.4 equiv.)was added and stirring was continued for 3 hours. The reaction mixturewas poured into buffer (700 mL) and extracted with EtOAc. The organiclayer was dried over Na₂ SO₄ and evaporated. Flash chromatography of theresidue on silica using EtOAc:toluene 2.5:97.5 afforded the titlecompound.

¹ H NMR (CDCl₃) δ (ppm): 3.37 (s, 3H), 3.48 (s, 3H), 3.93 (s, 3H), 7.29(d, 1H), 7.48 (dd, 1H), 7.75 (broad s, 1H), 7.95 (d, 1H).

Step 6 Preparation of S-(3-methoxycarbonyl)phenyl)dimethylcarbamothioate

The product of step 5 (8.452 g, 35.3 mmoles) was heated to reflux for 5days in dichlorobenzene (50 mL). Flash chromatography of the reactionmixture on silica using EtOAc:toluene 5:95 and 10:90 yielded the titleproduct.

¹ H NMR (CDCl₃) δ (ppm): 3.05 (broad s, 3H), 3.12 (broad s, 3H), 3.91(s, 3H), 7.48 (dd, 1H), 7.70 (d, 1H), 8.08 (d, 1H), 8.18 (broad s, 1H).

Step 7 Preparation of methyl 3-mercaptobenzoate

To the product of step 6 (6.767 g, 28.3 mmoles) in MeOH (23 mL), MeONa(1.74M in MeOH, 33 mL, 2 equiv.) was added and the solution was stirredat room temperature 8 hours and kept at 5° C. for 3 days. NH₄ OAc (600mL) was added, followed by HCl (1N, 60 mL). Extraction with EtOAc,drying of the organic phase over Na₂ SO₄ and flash chromatography of theresidue on silica with EtOAc:hexane:AcOH 4:96:1 yielded the title thiol.

¹ H NMR (CDCl₃) δ (ppm): 3.55 (s, 1H), 3.92 (s, 3H), 7.31 (d, 1H), 7.46(d, 1H), 7.82 (d, 1H), 7.95 (broad s, 1H).

Step 8 Preparation of methyl6-(3-cyanophenyl)-6-(3-(methoxycarbonyl)phenylthio)-3-methylhexanoate

The cyanostyrene of step 4 (506 mg, 2.08 mmoles) and the thiol of step 7(449 mg, 1.3 equiv.) were mixed together in CH₂ Cl₂ (20 mL). AlCl₃ (1.16g, 4.2 equiv.) was added and the mixture was stirred at room temperature1.5 hours. At 0° C., 25% aqueous NH₄ OAc was added. Extraction withEtOAc and flash chromatography of the residue from the dried organicphase on silica with EtOAc:hexane 15:85 and 20:80 afforded the titlecompound.

¹ H NMR (CDCl₃) δ (ppm): 0.93 (2d, 3H). 1.02-1.55 (m, 2H), 1.78-2.36 (m,5H), 3.66 (2s, 3H), 3.94 (s, 3H), 4.13 (dd, 1H), 7.22-7.53 (m, 6H), 7.88(broad s, 2H).

Step 9 Preparation of methyl6-(3-formylphenyl)-6-(3-(methoxycarbonyl)phenylthio)-3-methylhexanoate

HCl gas was bubbled into a suspension of SnCl₂ (2.769 g, 9 equiv.) inether (16 mL) until obtention of 2 liquid phases. The nitrile of step 8(670 mg, 1.628 mmoles) in toluene (3 mL) was then added. HCl was bubbledinto the mixture for 30 minutes and occasionally during a further 5hours. At 0° C., water (˜20 mL) was added to the flask and the mixturewas stirred at room temperature until obtention of a clear reactionmixture (˜5-10 minutes). The reaction mixture was then poured intoEtOAc:25% aqueous NH₄ OAc 1:1 (˜500 mL) and the resulting suspension wasstirred overnight, filtered through celite and extracted with EtOAc. Theorganic layer was dried over Na₂ SO₄ and evaporated. Flashchromatography of the residue on silica using EtOAc:hexane 15:85 and20:80 yielded the title aldehyde.

¹ H NMR (CDCl₃) δ (ppm): 0.92 (2d, 3H), 1.04-1.55 (m, 2H), 1.84-2.34 (m,5H), 3.62 (2s, 3H), 3.90 (s, 3H), 4.21 (t, 1H), 7.20-7.54 (m, 4H), 7.72(broad s, 2H), 7.84 (d, 1H), 7.89 (s, 1H).

Step 10 Preparation of methyl6-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-6-(3-(methoxycarbonyl)phenylthio)-3-methylhexanoate

At -78° C., BuLi (1.6M in hexanes, 1.0 mL, 1.2 equiv.) was addeddropwise to a suspension of((7-chloroquinolin-2-yl)methyl)triphenylphosphonium bromide (EP 233,763,Example 4, step 2) (926 mg, 1.3 equiv.) in THF (9 mL) and the suspensionwas stirred at this temperature for 1 hour. The benzaldehyde of step 9(566 mg, 1.364 mmoles) in THF (5 mL) was then added dropwise. Themixture was stirred at -78° C. for 15 minutes and at room temperaturefor 2 hours. It was quenched with 25% aqueous NH₄ OAc and extracted withEtOAc. The organic layer was dried over Na₂ SO₄, filtered through silicaand evaporated. Flash chromatography of the residue using EtOAc:hexane15:85 and 20:80 yielded the title diester.

¹ H NMR (CD₃ COCD₃) δ (ppm): 0.85 (2d, 3H), 1.07-1.56 (m, 2H), 1.83-2.30(m, 5H), 3.53 (2s, 3H), 3.80 (s, 3H), 4.45 (t, 1H), 7.30-7.58 (m, 7H),7.67-7.98 (m, 7H), 8.32 (d, 1H).

Step 11

To the diester of step 10 (722 mg, 1.26 mmoles) in THF:MeOH 1:1 (12 mL),LiOH 1.0N (3.8 mL, 3 equiv.) was added and the mixture was stirred for28 hours. 25% aqueous NH₄ OAc was then added and the mixture wasacidified to pH 5 with HCl. Extraction with EtOAc, drying of the organiclayer over Na₂ SO₄ and flash chromatography of the residue on silicausing EtOAc:toluene:AcOH 30:70:1 yielded the title diacid.

¹ H NMR (CD₃ COCD₃) δ (ppm): 0.92 (2d, 3H), 1.14-1.65 (m, 2H), 1.88-2.16(m, 4H), 2.21-2.38 (m, 1H), 4.50 (t, 1H), 7.30-7.62 (m, 7H), 7.70-8.03(m, 7H), 8.32 (d, 1H).

EXAMPLE 93-((3-((7-chloroquinolin-2-ylmethyl)oxy)phenyl)(2-(dimethylcarbamoyl)ethylthio)methyl)benzoicacid, sodium salt Step 1 Preparation of methyl3-[(3-((7-chloroquinolin-2-ylmethyl)oxy)phenyl)hydroxymethyl]benzoate

To a suspension of 3-bromobenzoic acid (905 mg) in THF (25 cc) at -78°C. was added 1.6M BuLi (6.25 cc) and the mixture was stirred for 1/2 hrat -78° C. A solution of3-((7-chloroquinolin-2-ylmethyl)oxy)benzaldehyde (EP 233,763, Example16, step 1) (1.49 g) in THF (25 cc) was added dropwise and allowed toreact for 1 hr at -78°. 25% aqueous NH₄ OAc (25 cc) and acetic acid (3cc) were added at -78° and the mixture allowed to warm to 25° C., atwhich temperature it was extracted with ethyl acetate (3×25 cc). Theorganic layer was washed with brine and the solvents were removed invacuo. The residue was taken up in dry 10% HCl in MeOH for 16 hrs atroom temperature. Most of the MeOH was removed in vacuo and the residuepartitioned between 25% aqueous NH₄ OAc (10 cc) and ethyl acetate (3×10cc). The organic layer was washed with brine and the solvents removed invacuo. The residue was purified by chromatography to afford the titlecompound.

p.m.r. (CD₃ COCD₃) δ (ppm): 8.3-8.4 (d, 1H), 6.9-8.1 (m, 12H), 5.85-5.9(d, 1H), 5.35 (s, 2H), 5.1 (d, 1H), 3.85 (s, 3H).

Step 2 Preparation of methyl3-((3-((7-chloroquinolin-2-ylmethyl)oxy)phenyl)(2-(dimethycarbamoyl)ethylthio)methyl)benzoate

To a solution of the alcohol (step 1) (70 mg) at 25° C. and3-mercapto-N,N-dimethylpropionamide (66 mg) in dichloroethane (2 cc) wasadded AlCl₃ (212 mg) and the gummy suspension stirred for 1/2 hr afterwhich time 25% aqueous NH₄ OAc (5 cc) was added. Organic materials wereextracted with ethyl acetate and the organic layer washed with brine andthe solvents removed in vacuo. The residue was purified bychromatography to afford the title compound which was used as such inthe next step.

Step 3

To a solution of the ester (step 2) (244 mg) in MeOH (1 cc) and THF (3cc) was added 2N NaOH (750 μL) and the mixture stirred 3 hrs at 25° C.after which the solvents were removed in vacuo. The residue waspartitioned between 25% aqueous NH₄ OAc (10 cc) containing AcOH (2 cc)and ethyl acetate (25 cc). The organic layer was washed with brine andthe solvent removed to give a residue which was purified bychromatography. To the acid obtained was added 1 equivalent of NaOH andthe mixture freeze dried to afford the title compound.

p.m.r. (CD₃ COCD₃) δ (ppm): 6.9-8.4 (m, 13H), 5.5 (s, 1H), 5.35 (s, 2H),2.9 (s, 3H), 2.8 (s, 3H), 2.5-2.7 (m, 4H).

EXAMPLE 103-((3-carboxyphenylthio)(3-(2-(7-chloroquinolin-2-yl)-ethenyl)phenyl)methyl)benzoicacid Step 1 Preparation of3-((3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)(3-methoxycarbonylphenylthio)methyl)benzoicacid

To a suspension of the hydroxyacid of Example 5, step 1 (1.032 g, 2.48mmoles) in CH₂ Cl₂ (25 mL), methyl 3-mercaptobenzoate (Example 8, step7, 545 mg, 1.3 equiv.) and 2,6-di-tert-butyl-4-methylphenol (106 mg, 0.2equiv.) were added. At 0° C., AlCl₃ (1.290 g, 3.9 equiv.) was added andthe reaction mixture was stirred at 0° C. 1.3 hours. THF and 25% aqueousNH₄ OAc were then added and the mixture was stirred at room temperaturefor 3 hours. The mixture was acidified to pH 5 with acetic acid and wasextracted with EtOAc. The organic layer was dried over Na₂ SO₄ andevaporated. Flash chromatography of the residue on silica usingEtOAc:toluene:AcOH 10:90:1 yielded the title compound (contaminated by adiaddition product), which was used as such in the next step.

Step 2

To the mixture of step 1 (400 mg containing 460 μmoles of monoadditionproduct and 153 μmoles of diaddition product) in THF:MeOH 1:1 (6 mL),LiOH 1.0N (2 mL) was added and the reaction mixture was stirred for 2days. 25% aqueous NH₄ OAc was then added and the mixture was acidifiedwith AcOH and extracted with EtOAc. Drying the organic phase over Na₂SO₄ and flash chromatography of the residue on silica usingEtOAc:toluene:AcOH 20:80:1 and 30:70:1 yielded the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 6.17 (s, 1H), 7.32-7.68 (m, 8H), 7.78-8.08(m, 9H), 8.27 (s, 1H), 8.31 (d, 1H).

EXAMPLE 113-((3-((7-chloroquinolin-2-ylmethyl)oxy)phenyl)(2-(t-butylcarbamoyl)ethylthio)methyl)benzoicacid sodium salt Step 1 Preparation of methyl3-((3-((7-chloroquinolin-2-ylmethyl)oxy)phenyl)(2-carboxyethylthio)methyl)benzoate

To a 0° C. solution of the alcohol (Example 9, step 1) (475 mg) and3-mercaptopropionoic acid (160 mg) in dichloroethane (15 cc), AlCl₃ (532mg), was added portion-wise and the suspension was stirred for 1/2 hr at0° C. after which time 25% aqueous NH₄ OAc (10 cc) was added. Theorganic materials were extracted with ethyl acetate (3×10 cc), theorganic layer washed with brine and the solvents removed in vacuo toyield a residue which was purified by chromatography to afford the titlecompound.

p.m.r. (CD₃ COCD₃) δ (ppm): 6.9-8.4 (m, 13H), 5.5 (s, 1H), 5.35 (s, 2H),3.85 (s, 3H), 2.5-2.7 (m, 4H).

Step 2 Preparation of methyl3-((3-((7-chloroquinolin-2-ylmethyl)oxy)phenyl)(2-(t-butylcarbamoyl)ethylthio)methyl)benzoate

To a 0° solution of the acid (step 1) (522 mg) in dichloromethane (25cc), acetonitrile (7 cc) and triethylamine (202 mg) was added2-chloro-1-methylpyridinium iodide (511 mg) and the mixture left toreact for 1.5 hrs at 0° C. Then t-butylamine (366 mg) was added and themixture stirred at 25° C. for 16 hrs. 25% aqueous NH₄ OAc (25 cc) wasadded and the mixture extracted with ethyl acetate (3×25 cc). Thecombined organic layers were washed with brine and the solvents removedin vacuo. The residue was purified by chromatography to afford the titlecompound.

p.m.r. (CD₃ COCD₃) δ (ppm): 6.9-8.4 (m, 13H), 6.75 (bs, 1H), 5.45 (s,1H), 5.35 (s, 2H), 3.85 (s, 3H), 2.3-2.65 (m, 4H), 1.3 (s, 9H).

Step 3

To a solution of the ester (step 2) (327 mg) in MeOH (1 cc) and THF (3cc) was added 2N NaOH (850 μL) and the reaction stirred for 16 hrs at25° C. 25% aqueous NH₄ OAc (10 cc) and acetic acid (1 cc) were added andthe organic material extracted with ethyl acetate (3×10 cc). The organiclayer was washed with brine and the solvents removed in vacuo to givethe acid which was treated with one equivalent of NaOH and freeze driedto afford the title compound.

p.m.r. (CD₃ COCD₃) δ (ppm): 6.8-8.3 (m, 14H), 5.25 (s, 2H), 5.2 (s, 1H),2.2-2.6 (m, 4H), 1.25 (s, 9H).

EXAMPLE 125-((3-((7-chloro-2-quinolinyl)methoxy)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)-3-pyridine-carboxylicacid, sodium salt Step 1 Preparation of methyl5-((3-((7-chloro-2-quinolinyl)methoxy)phenyl)-hydroxymethyl)-3-pyridinecarboxylate

To a -100° C. suspension of 3-bromonicotinic acid (1.21 g) in THF (25c.c.) was added BuLi (1.6M in hexanes, 12 mmoles); after 45 min therewas added a solution of the aldehyde from EP 233,763, Example 16, Step 1(1.48 g), in THF (25 c.c.) and the mixture was stirred 1.5 hr at -78° C.It was then poured onto 25% aqueous NH₄ OAc and 1 c.c. of conc. AcOH wasadded; the product was extracted with ethyl acetate, washed with brine,dried with MgSO₄ and the solvents removed in vacuo. The residue waspurified by chromatography to yield the carboxylic acid which wasesterified with 10% HCl in MeOH at r.t. After removal of most of theMeOH, 25% aqueous NH₄ OAc was added and the product extracted with ethylacetate, washed with brine and the solvents removed in vacuo to yieldthe title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 3.90 (s, 3H), 5.30 (s, 2H), 5.45 (d, 1H),6.00 (bs, 1H), 6.90-9.00 (m, 12H).

Step 2 Preparation of methyl5-((3-((7-chloro-2-quinolinyl)-methoxy)phenyl)-chloromethyl)-3-pyridinecarboxylate

To a r.t. solution of the alcohol (Step 1) (217 mg) in dichloromethane(10 c.c.) and carbon tetrachloride (5 c.c.) was added tri-n-octylphosphine (650 mg) and the reaction was stirred for 1.5 hr. The reactionproducts were preabsorbed on SiO₂ and the title compound purified bychromatography.

¹ H NMR (CD₃ COCD₃) δ (ppm): 3.90 (s, 3H), 5.40 (s, 2H), 6.55 (s, 1H),7.05-9.10 (m, 12H).

Step 3 Preparation of methyl5-((3-((7-chloro-2-quinolinyl)-methoxy)phenyl)((3-dimethylamino-3-oxopropyl)thio)-methyl)-3-pyridinecarboxylate

To a solution of the chloride (Step 2) (122 mg) and N,N-dimethyl3-mercaptopropionamide (45 mg) in acetonitrile (10 c.c.) was addedcesium carbonate (440 mg) and the mixture was heated to 80° C. for 3hrs. The reaction products were pre-absorbed on SiO₂ and the titlecompound purified by chromatography.

¹ H NMR (CD₃ COCD₃) δ (ppm) 2.50-2.70 (m, 4H), 2.80 (s, 3H), 2.90 (s,3H), 3.90 (s, 3H), 5.40 (s, 2H), 5.60 (s, 2H), 6.95-9.00 (m, 12H).

Step 4

To a 0° C. solution of the ester (Step 3) (85 mg) in THF (3 c.c.) andMeOH (1 c.c.) was added 2N NaOH (0.25 c.c.) and the mixture was stirredat r.t. for 3 hrs. 25% aqueous NH₄ OAc was added followed by conc. AcOH(3 drops) and the mixture was extracted with ethyl acetate; the organiclayer was washed with brine, dried with MgSO₄ and the solvents removedin vacuo. To the residue in ethanol (1 c.c.) was added 2N NaOH (77 μL)and the solution freeze dried to yield the title compound.

¹ H NMR (CD₃ COCD₃ ·DMSO) δ (ppm): 2.40-2.70 (m, 4H), 2.80 (s, 3H), 2.90(s, 3H), 5.40 (s, 2H), 6.90-9.00 (m, 12H).

EXAMPLE 143,3'-(((3-((7-Chloro-2-quinolinyl)methoxy)phenyl)methylene)bis(thio))bis(benzoicacid), disodium salt Step 1 Preparation of dimethyl3,3'-(((3-((7-chloro-2-quinolinyl)methoxy)phenyl)methylene)bis(thio))bis(benzoate)

At room temperature (r.t.), BF₃ ·Et₂ O (270 μL, 3.2 equiv.) was slowlyadded to a mixture of methyl 3-mercaptobenzoate (Example 8, Step 7; 269mg, 2.2 equiv.) and 3-((7-chloro-2-quinolinyl)methoxy)benzaldehyde (EP233,763, Example 16, Step 1; 204 mg) in CH₂ Cl₂ (3.5 mL). The reactionmixture was stirred 2.5 hours and was quenched at 0° C. with 25% aq. NH₄OAc. Extraction with EtOAc, drying over Na₂ SO₄ and flash chromatographyof the residue using EtOAc: toluene 5:95 yielded the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 3.87 (s, 6H), 5.33 (s, 2H), 6.05 (s, 1H),6.99 (d, 1H), 7.10-7.30 (m, 3H), 7.40 (t, 2H), 7.55-7.70 (m, 4H), 7.85(d, 2H), 7.95-8.05 (m, 4H), 9.37 (d, 1H).

Step 2

Using the procedure of Example 8, Step 11, the diester of Step 1 washydrolyzed to the diacid. The diacid was dissolved in ethanol and 2equiv. of NaOH 1.000N were added. The solvents were removed in vacuo andthe residue was taken up in water and freeze-dried.

Anal. calc'd for C₃₁ H₂₀ ClNO₅ S₂ Na₂ ·H₂ O: C, 57.28; H, 3.41; N, 2.15;S, 9.86; Cl, 5.45; Na, 7.07. Found: C, 57.18; H, 3.31; N, 2.00; S,11.01; Cl, 5.34; Na, 6.35.

EXAMPLE 233-(((4-Carboxyphenyl)thio)(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)methyl)benzoicacid, disodium salt Step 1 Preparation of methyl 4-mercaptobenzoate

4-Mercaptobenzoic acid (J. Org. Chem., 1962, 27, 2835; 1.72 g) and 98%H₂ SO₄ (0.7 mL) were mixed together in MeOH (55 mL) for 4 days. At 0°C., 25% aq. NH₄ OAc (500 mL) was then added and the ester was extractedwith EtOAc, dried over Na₂ SO₄ and the residue was purified byfiltration through silica using EtOAc:toluene 10:90.

¹ H NMR (CDCl₃) δ (ppm): 3.62 (s, 1H), 3.90 (s, 3H), 7.28 (d, 2H), 7.89(d, 2H).

Step 2

Using the procedure of Example 10, but substituting methyl3-mercaptobenzoate by methyl 4-mercaptobenzoate from Step 1, the titlecompound (free diacid) was obtained. It was then converted to thedisodium salt using the procedure of Example 14, Step 2.

Anal. calc'd for C₃₂ H₂₀ ClNO₄ SNa₂ ·2.8 H₂ O: C, 59.46; H, 3.99; N,2.17; S, 4.96; Cl, 5.48; Na, 7.11. Found: C, 59.40; H, 4.21; N, 2.10; S,5.03; Cl, 5.59; Na, 6.37.

EXAMPLE 243-((3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)((4-(dimethylaminocarbonyl)phenyl)thio)methyl)benzoicacid, sodium salt Step 1 Preparation of N,N-dimethyl 4-mercaptobenzamide

To P₂ O₅ (411 mg, 0.5 equiv.) in DMF (4 mL), 4-mercaptobenzoic acid (J.Org. Chem., 1962, 27, 2835; 883 mg) was added and the mixture was heatedat reflux for 10 hours (see Monatsh Chem., 1968, 99, 1799). Water andEtOAc were added and the resulting mixture was stirred until completedecomposition of polyphosphoric acid. The organic layer was separated,dried over Na₂ SO₄ and concentrated. The benzamide was purified by flashchromatography using EtOAc:toluene:AcOH 15:85:1 and 25:75:1.

¹ H NMR (CDCl₃) δ (ppm): 3.00 (br s, 3H), 3.10 (br s, 3H), 3.54 (br s,1H), 7.22-7.38 (m, 4H).

Step 2

Using the procedure of Example 5, but substituting N,N-dimethyl3-mercaptopropanamide by the thiol of Step 1, the title compound (freeacid) was obtained (the reaction conditions for the alcohol substitutionby the thiol were 0° C. 4 hours, then r.t. 30 min). It was thenconverted to the sodium salt as in Example 14, Step 2 (only one equiv.of NaOH was used).

Anal calc'd for C₃₄ H₂₆ ClN₂ O₃ SNa·1.5H₂ O: C, 65.02; H, 4.65; N, 4.46;S, 5.10; Cl, 5.64; Na, 3.66. Found: C, 65.03; H, 4.61; N, 4.28; S, 5.56;Cl, 5.93; Na, 3.37.

EXAMPLE 253-(2-((2-Carboxyethyl)thio)-2-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)ethyl)benzoicacid Step 1 Preparation of 1-methoxy-3-vinylbenzene

At -78° C., BuLi 1.6N (29.8 mL, 1.3 equiv.) was added dropwise to asuspension of methyltriphenylphosphonium bromide (18.4 g, 1.4 equiv.) inTHF (130 mL) and the mixture was stirred at r.t. 30 min. At -78° C.,3-methoxybenzaldehyde (4.5 mL) was then added and the mixture wasstirred at r.t. 2 hours. After quenching with 25% aq. NH₄ OAc, the titlecompound was extracted with EtOAc, dried over Na₂ SO₄ and purified byfiltration through silica using EtOAc:hexane 10:90.

Step 2 Preparation of (3-methoxyphenyl)oxirane

At 0° C., m-chloroperbenzoic acid (82%, 10.6 g, ˜1.4 equiv.) was addedto the product of Step 1 in CH₂ Cl₂ (185 mL). The mixture was stirred at0° C. for 30 min. and at r.t. for 2 hours. 10% Aq. Na₂ CO₃ was thenadded, the phases were separated and the aqueous was layer extractedwith ether. The combined organic phases were dried over Na₂ SO₄ andconcentrated. The title compound was purified by distillation: B.P.130°-136° C./16 mm Hg.

Step 3 Preparation of1-bromo-3-((diphenyl(2-methyl-2-propyl)silyloxy)methyl)benzene

3-Bromobenzyl alcohol (15.00 g, 80.2 mmoles),tert-butylchlorodiphenylsilane (25 mL, 1.2 equiv.),4-(dimethylamino)pyridine (1.06 g, 0.1 equiv.) and triethylamine (22 mL,2 equiv.) were mixed together in CH₂ Cl₂ (200 mL). After 20 hours ofstirring, 25% Aq. NH₄ OAc was added and the phases were separated. Theaqueous layer was extracted with EtOAc and the organic phases werecombined, dried over Na₂ SO₄ and concentrated. The title compound waspurified by filtration through silica using ether:hexane 5:95.

¹ H NMR (CDCl₃) δ (ppm): 1.10 (s, 9H), 4.73 (s, 2H), 7.14-7.30 (m, 2H),7.32-7.53 (m, 8H), 7.67 (dd, 4H).

Step 4 Preparation of1-(3-methoxyphenyl)-2-(3-((diphenyl(2-methyl-2-propyl)silyloxy)methyl)phenyl)ethanol

At -78° C., BuLi 1.6M (47 mL) was added dropwise to the bromide of Step3 (31.77 g, 75 mmoles) in THF (100 mL). The mixture was stirred at -20°C. for 10 min. and was added, via a cannula, to a cooled (-20° C.)suspension of CuCN (3.68 g) in THF (25 mL); a solution was obtained.(3-Methoxyphenyl)oxirane from Step 2 (1.8 g, 12 mmoles) was dissolved inTHF (20 mL) and cooled to -78° C. It was then added, via a cannula, tothe cooled (-20° C.) solution of cuprate. The mixture was stirred at-20° C. for 1 hour and at r.t. for 3 hours. Saturated NH₄ Cl containing10% NH₄ OH was added and stirring was continued for 30 min. Water wasthen added and the desired compound was extracted with EtOAc, dried overNa₂ SO₄ and purified by flash chromatography on silica usingEtOAc:hexane 10:90, 15:85 and 25:75. (See also J. Am. Chem. Soc., 1982,104, 2305 for the cuprate addition to epoxides.)

¹ H NMR (CDCl₃) δ (ppm): 1.10 (s, 9H), 1.94 (d, 1H, OH), 2.94 (dd, 1H),3.04 (dd, 1H), 3.80 (s, 3H), 4.76 (s, 2H), 4.87 (m, 1H), 6.82 (br d,1H), 6.90-6.98 (m, 2H), 7.12 (m, 1H), 7.17 (s, 1H), 7.25-7.30 (m, 3H),7.33-7.47 (m, 6H), 7.70 (dd, 4H).

Step 5 Preparation of1-chloro-1-(3-methoxyphenyl)-2-(3-((diphenyl(2-methyl-2-propyl)silyloxy)methyl)phenyl)ethane

To the benzyl alcohol of Step 4 (1.116 g, 2.25 mmoles) in CH₂ Cl₂ :CCl₄1:2 (10 mL) cooled to 0° C., trioctylphosphine (2.508 g, 3 equiv.) wasadded and the mixture was stirred at r.t. for 4 hours. Silica gel wasadded and the mixture was stirred 5 min. It was then poured onto a flashchromatography column and eluted with EtOAc:hexane 5:95. The titlecompound thus obtained was used as such for the next step.

Step 6 Preparation of methyl3-((1-(3-methoxyphenyl)-2-(3-((diphenyl(2-methyl-2-propyl)silyloxy)methyl)phenyl)ethyl)thio)propanoate

The chloride of Step 5 was dissolved in CH₃ CN (15 mL). CsCO₃ (2.221 g)and methyl 3-mercaptopropanoate (340 μL) were added and the resultingmixture was stirred at 65° C. for 2 hours and at reflux for 2 hours.EtOAc was added and the suspension was filtered through celite. Flashchromatography of the residue (after evaporation) on silica usingEtOAc:hexane 7.5:92.5 and 10:90 yielded1-(3-methoxyphenyl)-2-(3-((diphenyl(2-methyl-2-propyl)silyloxy)methyl)phenyl)ethene(the elimination product), followed by the title compound.

¹ H NMR (CDCl₃) δ (ppm): 1.10 (s, 9H), 2.41 (t, 2H), 2.56 (t, 2H), 3.11(d, 2H), 3.63 (s, 3H), 3.77 (s, 3H), 4.01 (t, 1H), 4.70 (s, 2H), 6.74(dd, 1H), 6.83 (m, 2H), 6.94 (m, 1H), 7.04 (br s, 1H), 7.13-7.21 (m,3H), 7.34-7.47 (m, 6H), 7.68 (d, 4H).

Step 7 Preparation of methyl3-((1-(3-methoxyphenyl)-2-(3-(hydroxymethyl)phenyl)ethyl)thio)propanoate

The silyl ether of Step 6 (469 mg, 783 μmoles), Bu₄ NF (1.0M in THF, 1.6mL) and acetic acid (160 μL) were mixed together in THF (4 mL) for 8hours. 25% Aq. NH₄ OAc was added and the title compound was extractedwith EtOAc, dried over Na₂ SO₄ and purified by flash chromatography onsilica using EtOAc:toluene 20:80.

¹ H NMR (CDCl₃) δ (ppm): 1.83 (br s, 1H, OH), 2.43 (t, 2H), 2.53 (t,2H), 3.12 (d, 2H), 3.65 (s, 3H), 3.80 (s, 3H), 4.02 (t, 1H), 4.62 (s,2H), 6.78 (d, 1H), 6.80-6.90 (m, 2H), 7.00 (d, 1H), 7.08 (s, 1H),7.12-7.25 (m, 3H).

Step 8 Preparation of methyl3-(2-((2-(methoxycarbonyl)ethyl)thio)-2-(3-methoxyphenyl)ethyl)benzoate

Using the procedure of Example 1, Steps 3 and 4, the benzyl alcohol ofStep 7 was oxidized to the title ester.

¹ H NMR (CDCl₃) δ (ppm): 2.43 (t, 2H), 2.56 (t, 2H), 3.14 (m, 2H), 3.63(s, 3H), 3.79 (s, 3H), 3.90 (s, 3H), 4.03 (t, 1H), 6.78 (d, 1H),6.80-6.88 (m, 2H), 7.17-7.30 (m, 3H), 7.80 (s, 1H), 7.85 (d, 1H).

Step 9 Preparation of methyl3-(2-(3-hydroxyphenyl)-2-((2-(methoxycarbonyl)ethyl)thio)ethyl)benzoate

At -78° C., BBr₃ (1.0M in CH₂ Cl₂, 2 mL, 4 equiv.) was added dropwise toa solution of the methyl ether of Step 8 (193 mg, 497 μmoles) and Et₃ N(14 μL, 0.2 equiv.) in CH₂ Cl₂ (2 mL). The reaction mixture was stirred1.5 hours at -20° C. and quenched with 25% aq. NH₄ OAc.. Extraction withEtOAc, drying over Na₂ SO₄ and flash chromatography of the residue onsilica using EtOAc:toluene 7.5:92.5 and 12.5:87.5 yielded the titlephenol.

¹ H NMR (CDCl₃) δ (ppm): 2.43 (t, 2H), 2.56 (t, 2H), 3.14 (m, 2H), 3.65(s, 3H), 3.91 (s, 3H), 4.00 (t, 1H), 5.50 (br s, 1H, OH), 6.72 (d, 1H),6.75-6.83 (m, 2H), 7.10-7.30 (m, 3H), 7.80 (s, 1H), 7.85 (d, 1H).

Step 10 Preparation of methyl3-(2-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-2-((2-(methoxycarbonyl)ethyl)thio)ethyl)benzoate

The phenol of Step 9 (142 mg, 379 μmoles),2-(bromomethyl)-7-chloroquinoline (143 mg, 1.5 equiv.) and K₂ CO₃(milled, 105 mg, 2 equiv.) were mixed together in acetone (4 mL) andheated at reflux 8 hours. EtOAc was then added and the mixture wasfiltered through a small pad of silica gel. Flash chromatography of theresidue using EtOAc:toluene 5:95 and 7.5:92.5 afforded the titlecompound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.42 (m, 2H), 2.53 (m, 2H), 3.20 (m, 2H),3.58 (s, 3H), 3.85 (s, 3H), 4.27 (t, 1H), 5.37 (s, 2H), 6.90-7.00 (m,2H), 7.13 (br s, 1H), 7.21 (t, 1H), 7.27-7.37 (m, 2H), 7.60 (dd, 1H),7.70 (d, 1H), 7.74-7.80 (m, 2H), 8.02 (d, 1H), 8.05 (br s, 1H), 8.40 (d,1H).

Step 11

Using the procedure of Example 8, Step 11, the diester of Step 10 washydrolyzed to the title diacid.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.42 (m, 2H), 2.55 (m, 2H), 3.22 (m, 2H),4.30 (t, 1H), 5.37 (s, 2H), 6.92 (dd, 1H), 6.98 (d, 1H), 7.15-7.35 (m,4H), 7.60 (dd, 1H), 7.70 (d, 1H), 7.80 (m, 2H), 8.01 (d, 1H), 8.05 (brs, 1H), 8.40 (d, 1H).

EXAMPLE 263-(1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-1-((2-carboxy-4-pyridinyl)thio)methyl)benzoicacid Step 1 Preparation of methyl3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)hydroxymethyl)benzoate

At 0° C., AcCl (10 mL) was added to MeOH (80 mL) and the solution wasstirred ≈30 min. at r.t. The hydroxyacid of Example 5, Step 1 (1.96 g,4.7 mmoles) was then added and the mixture was stirred at r.t. 4 days.It was then poured into 25% aq. NH₄ OAc (400 mL), THF (100 mL) and EtOAc(150 mL). The phases were separated and the aqueous layer was extractedtwice with EtOAc:THF 2:1. The combined extracts were dried over Na₂ SO₄.Flash chromatography of the residue using EtOAc:toluene 10:90 and 20:80yielded the title ester.

Step 2 Preparation of methyl3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)chloromethyl)benzoate

To the hydroxyester of Step 1 (307 mg, 714 μmoles) in CH₂ Cl₂ :CCl₄ 3:2(5 mL) was added dropwise trioctylphosphine (815 mg, 3 equiv.) and theresulting solution was stirred at r.t. 5 hours. 25% Aq. NH₄ OAc was thenadded and the title compound was extracted with EtOAc, dried over Na₂SO₄ and purified by flash chromatography on silica using EtOAc:toluene2.5:97.5.

¹ H NMR (CD₃ COCD₃) δ (ppm): 3.88 (s, 3H), 6.58 (s, 1H), 7.43-7.60 (m,5H), 7.73 (d, 1H), 7.80-8.01 (m, 7H), 8.20 (s, 1H), 8.33 (d, 1H).

Step 3 Preparation of methyl3-(1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-1-((2-carboxy-4-pyridinyl)thio)methyl)benzoate

A mixture containing the chloride of Step 2 (166 mg, 370 μmoles), Cs₂CO₃ (61 mg, 5 equiv.), 2-carboxy-4-mercaptopyridine (84 mg, 2 equiv.)and 2,6-di-tert-butyl-4-methylphenol (53 mg, 0.5 equiv.) in CH₃ CN (4mL) is stirred in the dark 20 hours. 25% Aq. NH₄ OAc was added and theproduct was extracted with EtOAc after acidification to pH 2, andpurified by flash chromatography.

Step 4

Using the procedure of Example 8, Step 11, the ester of Step 3 ishydrolyzed to the title acid.

EXAMPLE 273-(1-((2-carboxyphenyl)thio)-1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)methyl)benzoicacid, disodium salt Step 1 Preparation of methyl 2-mercaptobenzoate

A solution of HCl/MeOH was formed by the reaction of AcCl (35 mL) withMeOH (200 mL) at 0° C. Thiosalicylic acid (9.91 g, 64.3 mmoles) wasadded to this solution and the mixture was stirred at r.t. 7 days. Itwas then poured into 25% aq. NH₄ OAc (2.5 ). Extraction with EtOAc,drying over Na₂ SO₄ and flash chromatography of the residue on silicausing EtOAc:hexane 2.5:97.5 and 5:95 yielded the title ester.

¹ H NMR (CDCl₃) δ (ppm): 3.93 (s, 3H), 4.70 (s, 1H), 7.17 (m, 1H), 7.32(m, 2H), 8.02 (d, 1H).

Step 2

Using the procedure of Example 10, but substituting methyl3-mercaptobenzoate for methyl 2-mercaptobenzoate from Step 1 and doingthe hydrolysis Step 2 with NaOH at 50° C. 8 hours instead of with LiOHat r.t. 2 days, the title acid was obtained. The disodium salt was thenprepared using the procedure of Example 14, Step 2.

Anal. calc'd for C₃₂ H₂₀ ClNO₄ SNa₂ ·3H₂ O: C, 59.13; H, 4.03; N, 2.15;S, 4.93; Cl, 5.45; Na, 7.07 Found: C, 59.11; H, 3.97; N, 2.21; S, 5.18;Cl, 5.54; Na, 6.15

EXAMPLE 282-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-((2-carboxyethyl)thio)propyl)benzoicacid Step 1 Preparation of methyl2-(3-(3-methoxyphenyl)-2-propenyl)benzoate

Using the procedure of Example 1, Steps 1-4, with the modificationsbelow, the title compound (cis:trans mixture) was prepared. In Step 1,3-methoxybenzyl chloride was used in place of3-(bromomethyl)benzonitrile and the phosphonium salt was formed atreflux of CH₃ CN for 19 hours.

¹ H NMR (CDCl₃) δ (ppm): 3.80-4.10 (m, 8H), 5.80, 6.40 and 6.55 (m, 2H,cis:trans mixture), 6.70-6.97 (m, 3H), 7.15-7.50 (m, 4H), 7.90 (d, 1H).

Step 2 Preparation of methyl2-(3-((2-(methoxycarbonyl)ethyl)thio)-3-(3-methoxyphenyl)propyl)benzoate

Using the procedure of Example 1, Step 5, but doing the reaction at -10°C. for 20 minutes, the compound of Step 1 was converted to the titleproduct.

¹ H NMR (CDCl₃) δ (ppm): 2.12 (m, 2H), 2.46 (m, 2H), 2.59 (m, 2H), 2.88(m, 1H), 3.04 (m, 1H), 3.67 (s, 3H), 3.84 (m, 7H), 6.80 (d, 1H), 6.90(m, 2H), 7.17-7.28 (m, 3H), 7.40 (t, 1H), 7.87 (d, 1H).

Step 3

Using the procedure of Example 25, Steps 9-11, the preceding compoundwas converted to the title diacid.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.12 (m, 2H), 2.42 (m, 2H), 2.51 (m, 2H),2.87 (m, 1H), 3.03 (m, 1H), 3.93 (t, 1H), 5.40 (s, 2H), 6.97 (d, 1H),7.03 (d, 1H), 7.15-7.33 (m, 4H), 7.43 (t, 1H), 7.60 (d, 1H), 7.76 (d,1H), 7.90 (d, 1H), 8.00 (d, 1H), 8.06 (s, 1H), 8.41 (d, 1H).

EXAMPLE 292-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-((3-dimethylamino-3-oxopropyl)thio)propyl)benzoicacid, sodium salt Method A Step 1 Preparation of methyl2-(3-((3-dimethylamino-3-oxopropyl)thio)-3-(3-methoxyphenyl)propyl)benzoat

At -10° C., AlCl₃ (879 mg, 5.5 equiv.) was added to a solutioncontaining N,N-dimethyl 3-mercaptopropanamide (191 mg, 1.2 equiv.), thestyrene of Example 28, Step 1 (333 mg, 1.18 mmoles) and2,6-di-tert-butyl-4-methylphenol (53 mg, 0.2 equiv.) in CH₂ Cl₂ (12 mL).The resulting mixture was stirred in the dark at 0° C. for 3 hours andwas quenched with 25% aq. NH₄ OAc. Extraction with EtOAc, drying overNa₂ SO₄ and flash chromatography of the residue with acetone:toluene10:90 and 15:85 yielded the title product, which was used as such forthe next step.

Step 2 Preparation of methyl2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-((3-dimethylamino-3-oxopropyl)thio)propyl)benzoate

Using the procedures of Example 25, Steps 9 and 10, but avoiding the useof Et₃ N in Step 9, the product of Step 1 was converted to the titlecompound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.08 (m, 2H), 2.40 (m, 2H), 2.52 (m, 2H),2.75 (m, 1H), 2.80 (s, 3H), 2.90 (s, 3H), 2.94 (m, 1H), 3.80 (s, 3H),3.93 (t, 1H), 5.48 (s, 2H), 6.98 (d, 1H), 7.02 (d, 1H), 7.15-7.33 (m,4H), 7.43 (t, 1H), 7.60 (dd, 1H), 7.80 (m, 2H), 8.03 (d, 1H), 8.14 (brs, 1H), 8.50 (d, 1H).

Step 3

The ester of Step 2 (620 mg, 1.07 mmoles) was hydrolyzed with 3.3N NaOH(3.3 mL, 10 equiv.) in THF:MeOH 1:1 (11 mL) at r.t. for 24 hours. 25%Aqueous NH₄ OAc was added and the solution was acidified with AcOH.Extraction with EtOAc, drying over Na₂ SO₄ and flash chromatography ofthe residue on silica with acetone:toluene:AcOH 10:90:1 and 15:85:1yielded the title acid. It was then converted to the sodium salt as inExample 14, Step 2, but only one equiv. of NaOH was used.

Anal calc'd for C₃₁ H₃₀ ClN₂ O₄ SNa·0.5H₂ O: C, 62.67; H, 5.26; N, 4.72;S, 5.40; Cl, 5.97; Na, 3.87. Found: C, 62.86; H, 5.21; N, 4.53; S, 5.12;Cl, 5.87; Na, 3.62.

Method B Step 1 Preparation of3-((7-chloro-2-quinolinyl)methoxy)benzenemethanol

3-((7-Chloro-2-quinolinyl)methoxy)benzaldehyde (EP 233,763, Example 16,Step 1; 9.60 g, 32.24 mmoles) was dissolved in EtOH:THF 3:1 (215 mL). At0° C., NaBH₄ (1.21 g, 1 equiv.) was added and the mixture was stirred atr.t. 20 min. It was then poured into 25% aq. NH₄ OAc (500 mL) and EtOAc.Extractions with EtOAc, drying over Na₂ SO₄ and filtration throughsilica yielded the benzyl alcohol, which was used as such in the nextstep.

Step 2 Preparation of2-((3-(bromomethyl)phenoxy)methyl)-7-chloroquinoline

To the product of Step 1 and CBr₄ (13.90 g, 1.3 equiv.) in CH₂ Cl₂ (160mL) at 0° C., a solution of 1,2-bis(diphenylphosphino)ethane (DIPHOS,8.37 g, 0.65 equiv.) in CH₂ Cl₂ (75 mL) was added and the resultingmixture was stirred at 0° C. for 45 min. and at r.t. for 30 min. Etherwas then added and the mixture was filtered through a pad of silica andthe silica was washed with EtOAc:toluene 20:80 to yield the purebenzylic bromide.

¹ H NMR (CD₃ COCD₃) δ (ppm): 4.62 (s, 2H), 5.40 (s, 2H), 7.04 (d, 1H),7.08 (d, 1H), 7.21 (s, 1H), 7.30 (t, 1H), 7.60 (dd, 1H), 7.76 (d, 1H),8.02 (d, 1H), 8.05 (s, 1H), 8.42 (d, 1H).

Step 3 Formation of((3-((7-chloro-2-quinolinyl)methoxy)phenyl)methyl)triphenyl-phosphoniumbromide

The bromide of Step 2 (7.20 g, 22.3 mmoles) and triphenylphosphine (8.82g, 1.5 equiv.) were heated at reflux in CH₃ CN (75 mL) for 8 hours. Atr.t., ether was added and an oil separated, which crystallized ontrituration. The solid was filtered and was swished with ether for 20hours to yield the phosphonium salt.

¹ H NMR (CD₃ COCD₃ /CD₃ SOCD₃) δ 5.15 (s, 2H), 5.23 (d, 2H), 6.69 (d,1H), 6.77 (s, 1H), 7.02 (d, 1H), 7.19 (t, 1H), 7.56 (d, 1H), 7.62-7.80(m, 13H), 7.85-7.95 (m, 3H), 8.04 (s, 1H), 8.08 (d, 1H), 8.48 (d, 1H).

Step 4 Formation of2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-2-propenyl)benzenemethanol

At -10° C., potassium hexamethyldisilazide 0.65M in toluene (21 mL, 1.8equiv.) was added dropwise to a suspension of the phosphonium salt ofStep 3 (8.457 g, 13.53 mmoles, 1.8 equiv.) in THF (70 mL) and themixture was stirred at 0° C. for 30 min. At -78° C.,1H-3-hydroxy-3,4-dihydrobenzo(c)pyran (1.141 g, 7.60 mmoles) in THF (14mL) was added slowly. The mixture was allowed to warm to r.t. and wasstirred for a further 3 hours. 25% Aqueous NH₄ OAc was added and theproducts were extracted with EtOAc, dried over Na₂ SO₄ and purified byflash chromatography on silica using EtOAc:toluene 10:90 and 15:85. Thetitle compound was obtained as a cis:trans mixture and was used as suchfor the next step.

¹ H NMR (CD₃ COCD₃) δ (ppm): 3.60 (d, 2H), 4.55 and 4.72 (s, 2H), 5.37(s, 2H). 5.75 and 6.35-6.57 (m, 2H), 6.91 (d, 1H), 6.99 (d, 1H),7.12-7.30 (m, 5H), 7.43 (m, 1H), 7.60 (d, 1H), 7.73 (d, 1H), 8.00 (m,2H), 8.40 (d, 1H).

Step 5 Preparation of2-(3-(3-((7-chloro-2-quinolinyl)-methoxy)phenyl)-2-propenyl)benzaldehyde

To a solution of the benzylic alcohol of Step 4 (2.899 g, 6.20 mmoles)in EtOAc (120 mL) was added portionwise activated MnO₂ (10.15 g, approx.18 equiv.) and the reaction was followed by TLC (EtOAc:toluene7.5:92.5). When the reaction was completed (approx. 2 hours), themixture was filtered through silica, concentrated, and the title productwas purified by flash chromatography on silica using EtOAc:toluene2.5:97.5.

¹ H NMR (CD₃ COCD₃) δ (ppm): 4.00 (d, 2H), 5.35 (s, 2H), 5.72 and6.30-6.60 (m, 2H), cis:trans mixture), 6.90-8.10 (m, 12H), 8.39 (d, 1H),10.33 (s, 1H).

Step 6 Preparation of methyl2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-2-propenyl)benzoate

Using the procedures of Example 1, Step 4, but dissolving the aldehydeof Step 5 in hot THF before doing the reaction, the title compound wasobtained.

¹ H NMR (CD₃ COCD₃) δ (ppm): 3.70 and 3.82-3.95 (m, 5H, cis:transmixture), 5.38 (2s, 2H), 5.70 and 6.47 (2m, 2H), 6.87-8.05 (m, 12H),8.38 (2d, 1H).

Step 7

Using the procedure of Example 29, Method A, Steps 1 and 3, the productof Step 6 was converted to the title compound.

EXAMPLE 302,2'-(((3-((7-chloro-2-quinolinyl)methoxy)phenyl)methylene)bis(thio))bis(benzoicacid), disodium salt Step 1 Preparation of dimethyl2,2'-(((3-((7-chloro-2-quinolinyl)methoxy)phenyl)methylene)bis(thio))bis(benzoate)

Using the procedure of Example 14, Step 1 but using methyl2-mercaptobenzoate (Example 27, Step 1) instead of methyl3-mercaptobenzoate, the title diester was obtained. It was used as suchin the next step.

Step 2

The diester of Step 1 (603 mg, 980 μmoles) was stirred in MeOH:THF:H₂ O7:5:3 (15 mL) with NaOH (1 mL of 10 N) at 50° C. for 5 hours and at r.t.20 hours. The work up of the reaction and the formation of the titlecompound was the same as Example 14, Step 2.

Anal. calc'd for C₃₁ H₂₀ ClNO₅ S₂ Na₂ ·0.7: H₂ O: C, 57.75; H, 3.35; N,2.17; S, 9.95; Cl, 5.50; Na, 7.13. Found: C, 57.55; H, 3.39; N, 2.04; S,9.78; Cl, 5.67; Na, 6.67.

EXAMPLE 312-chloro-5-((3-((7-chloro-2-quinolinyl)methoxy)phenyl)-((3-dimethylamino-3-oxopropyl)thio)methyl)benzoicacid, sodium salt Step 1 Preparation of2-chloro-5-((3-((7-chloro-2-quinolinyl)methoxy)phenyl)hydroxymethyl)benzoicacid

To a suspension of 5-bromo-2-chlorobenzoic acid (1.004 g, 4.26 mmoles)in THF (20 mL) at -100° C., n-BuLi (5.3 mL of 1.6M, 2 equiv.) was addeddropwise and the mixture was stirred at -78° C. for 1.2 hours. At -100°C., a solution of 3-((7-chloro-2-quinolinyl)-methoxy)benzaldehyde (EP233,763, Example 16, Step 1 ; 1.253 g, 4.21 mmoles) in THF (15 mL) wasadded dropwise and the mixture was stirred 2 hours at -78° C. AcOH (2mL) was then added, followed by 25% aq. NH₄ OAc. The product wasextracted with EtOAc:THF 1:1, dried over Na₂ SO₄ and purified by flashchromatography on silica with EtOAc:toluene:AcOH 30:70:1.

¹ H NMR (CD₃ COCD₃) δ (ppm): 5.34 (s, 2H), 5.87 (s, 1H), 6.95 (dd, 1H),7.05 (d, 1H), 7.18 (s, 1H), 7.26 (t, 1H), 7.38 (d, 1H), 7.52 (dd, 1H),7.62 (dd, 1H), 7.72 (d, 1H), 7.94 (d, 1H), 8.01 (d, 1H), 8.03 (s, 1H),8.38 (d, 1H).

Step 2

To a suspension of the alcohol of Step 1 (279 mg, 614 μmoles) in CH₂ Cl₂(6 mL) at 0° C., N,N-dimethyl 3-mercaptopropanamide (97 mg, 1.15 equiv.)was added, followed by AlCl₃ (580 mg, 7 equiv.). The mixture was stirred2 hours at 0° C. and was quenched with 25% aq. NH₄ OAc, THF and AcOH.The product was extracted with EtOAc:THF 1:1, dried over Na₂ SO₄ andpurified by flash chromatography on silica using acetone:toluene:AcOH10:90:1, 20:80:1 and 30:70:1 sequentially. The sodium salt was formed asin Example 14, Step 2, but only one equiv. of NaOH was used.

Anal. calc'd for C₂₉ H₂₅ Cl₂ N₂ O₄ SNa·0.5 H₂ O: C, 58.01; H, 4.36; N,4,67; S, 5.34; Cl, 11.81; Na, 3.83. Found: C, 57.90; H, 4.62; N, 4.40;S, 5.56Cl, 11.91; Na, 3.68.

EXAMPLE 322,2'-(((3-((7-chloro-2-quinolinyl)methoxy)phenyl)-methylene)bis(thiomethyl))bis(benzoicacid), disodium salt Step 1 Preparation of ethyl2-(mercaptomethyl)benzoate

H₂ S was bubbled through a solution of KOH (290 mg, 1.2 equiv.) in MeOH(4 mL) at 0° C. until saturation. A solution of ethyl2-(chloromethyl)-benzoate and ethyl 2-(bromomethyl)benzoate(Tetrahedron, 1966, 22, 2107; 1.006 g of a 1:2 mixture, 4.28 mmoles) inMeOH (3 mL) was then added dropwise at -20° C. The mixture was warmed to0° C. for 1 hour and to r.t. for 2 hours. H₂ S was occasionally bubbledinto the reaction mixture during all this process. Addition of 25% aq.NH₄ OAc, extraction with EtOAc, drying over Na₂ SO₄ and distillation ofthe residue (80°-86° C./0.15 mm) yielded the title compound, which wasused as such for the next step.

Step 2

Using the procedure of Example 14, Step 1, but replacing methyl3-mercaptobenzoate by the thiol of Step 1, the diester of the titlecompound was obtained. It was then hydrolyzed using the procedure ofExample 30, Step 2 to yield the title compound.

Anal calc'd for C₃₃ H₂₄ ClNO₅ S₂ Na₂ ·0.5 H₂ O: C, 59.24; H, 3.77; N,2.09; S, 9.58; Cl, 5.30; Na, 6.87. Found: C, 59.34; H, 3.70; N, 2.09; S,10.13; Cl, 5.04; Na, 6.64.

EXAMPLE 332-((((3-((7-chloro-2-quinolinyl)methoxy)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)thio)methyl)-benzoicacid Step 1 Preparation ofN,N-dimethyl-3-(((acetylthio)(3-((7-chloro-2-quinolinyl)methoxy)phenyl)methyl)thio)propanamide

Using the procedure of Example 14, Step 1, but using 1.1 equiv. ofthiolacetic acid and 1.1 equiv. of N,N-dimethyl 3-mercaptopropanamideinstead of 2.2 equiv. of methyl 3-mercaptobenzoate, and adding BF₃ ·Et₂O at 0° C. instead of at r.t., the title compound was obtained. It wasused as such for the next step.

Step 2 Preparation of ethyl2-((((3-((7-chloro-2-quinolinyl)-methoxy)phenyl)((3-dimethylamino-3-oxopropyl)thio)-methyl)thio)methyl)benzoate

At -78° C., 1.26M MeONa (410 μL, 1.1 equiv.) was added dropwise to asolution of the mixed dithioketal of Step 1 (230 mg, 470 μmoles) in THF(5 mL) and the mixture was stirred at -78° C. for 15 min. Then, asolution of ethyl 2-(chloromethyl)-benzoate and ethyl2-(bromomethyl)benzoate (Tetrahedron, 1966, 22, 2107; 222 mg of a 1:2mixture, 2.13 equiv.) in THF (1 mL) was added. The mixture was stirredat -78° C. for 2.2 hours, then at -20° C. for 0.8 hour and at 0° C. for0.5 hour. Addition of 25% aq. NH₄ OAc, extraction with EtOAc, dryingover Na₂ SO₄ and flash chromatography of the residue on silica withEtOAc:toluene 40:60 yielded the title dithioketal.

¹ H NMR (CD₃ COCD₃) δ (ppm): 1.33 (t, 3H), 2.45 (t, 2H), 2.60-2.80 (m,2H), 2.82 (s, 3H), 2.89 (s, 3H), 4.07 (d, 1H), 4.15 (d, 1H), 4.30 (q,2H), 4.90 (s, 1H), 5.37 (s, 2H), 6.98 (dd, 1H), 7.03 (d, 1H), 7.16 (m,1H), 7.20-7.50 (m, 4H), 7.59 (d, 1H), 7.73 (d, 1H), 7.86 (d, 1H), 8.00(d, 1H), 8.03 (s, 1H), 8.40 (d, 1H).

Step 3

Using the procedures of Example 8, Step 11, the title acid was prepared.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.58 (t, 2H), 2.70 (m, 1H), 2.80-2.95 (m,1H), 2.88 (s, 3H), 2.94 (s, 3H), 4.11 (AB system, 2H), 4.98 (s, 1H),5.40 (s, 2H), 6.99 (dd, 1H), 7.06 (d, 1H), 7.15-7.47 (m, 5H), 7.58 (d,1H), 7.75 (d, 1H), 7.90 (d, 1H), 8.00 (d, 1H), 8.06 (s, 1H), 8.42 (d,1H).

EXAMPLE 343-((3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)((4-(dimethylamino)-4-oxopropyl)thio)methyl)benzoicacid Step 1 Preparation of methyl3-((acetylthio)(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)methyl)benzoate

Using the procedure of Example 26, Step 3, but replacing4-mercaptopyridine by thiolacetic acid (1.2 equiv.) and using 1 equiv.of 2,6-di-tert-butyl-4-methylphenol and 1.3 equiv. of CsCO₃, the titlethiolester was prepared.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.38 (s, 3H), 3.87 (s, 3H), 6.08 (s, 1H),7.45-7.55 (m, 5H), 7.64 (d, 1H), 7.70 (d, 1H), 7.75-8.00 (m, 6H), 8.09(s, 1H), 8.30 (d, 1H).

Step 2 Preparation of methyl3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)((4-(dimethylamino)-4-oxopropyl)-thio)methyl)benzoate

At -78° C., 1.26M MeONa (970 μL, 4 equiv.) is added to a mixture of thethiolester of Step 1 (147 mg, 301 μmoles) and N,N-dimethyl4-chlorobutanamide (2.9 equiv.) in THF (3 mL). The mixture is stirred at0° C. for 45 min., at r.t. for 15 min and then at 50° C. for 3 hours.Addition of 25% aq. NH₄ OAc, extraction with EtOAc:THF 1:1, drying overNa₂ SO₄ and flash chromatography of the residue on silica yields thetitle compound.

Step 3

The ester of Step 2 is hydrolyzed in THF:MeOH:H₂ O 2:4:1 (1 mL) with 3equiv. of 10N NaOH at r.t. for 23 hours. 25% aq. NH₄ OAc is added andthe product is extracted with EtOAc, dried over Na₂ SO₄ and purified byflash chromatography on silica.

EXAMPLE 352-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-((3-((2-methyl-2-propyl)amino)-3-oxopropyl)thio)propyl)-benzoicacid, sodium salt Step 1 Preparation of3-((1-(3-((7-chloro-2-quinolinyl)-methoxy)phenyl)-3-(2-(methylycarbonyl)phenyl)propyl)-thio)propanoicacid

To methyl2-(3-(3-((7-chloro-2-quinolinyl)-methoxy)phenyl)-2-propenyl)benzoate(Example 29, Method B, Step 6), 3-mercaptopropionic acid was added usingthe procedure of Example 29, Method A, Step 1 , to yield the titlecompound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.10 (m, 2H), 2.43 (m, 2H), 2.52 (m, 2H),2.70-3.00 (m, 2H), 3.80 (s, 3H), 3.95 (t, 1H), 5.42 (s, 2H), 7.00 (m,2H), 7.15-7.33 (m, 4H), 7.43 (t, 1H), 7.58 (d, 1H), 7.77 (d, 1H), 7.80(d, 1H), 7.97 (d, 1H), 8.04 (s, 1H), 8.39 (d, 1H).

Step 2 Preparation of methyl2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-((3-((2-methyl-2-propyl)amino)-3-oxopropyl)thio)propyl)benzoate

To a solution of the acid of Step 1 (385 mg, 700 μmoles) in CH₂ Cl₂ :CH₃CN 4:1 (20 mL) at 0° C., Et₃ N (290 μL, 2 equiv.) was added, followed by2-chloro-1-methylpyridinium iodide (535 mg, 2 equiv.) and the reactionmixture was stirred at 0° C. for 1.8 hours. Then, tert-butylamine wasadded and stirring was continued at r.t. 3 hours. Addition of 25% aq.NH₄ OAc, extraction with EtOAc, drying over Na₂ SO₄ and flashchromatography of the residue on silica, using EtOAc:toluene 20:80 and25:75 sequentially yielded the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 1.30 (s, 9H), 2.07 (m, 2H), 2.25 (t, 2H),2.50 (t, 2H), 2.70-3.00 (m, 2H), 3.80 (s, 3H), 3.90 (t, 1H), 5.32 (s,2H), 6.70 (br, s, 1H, NH), 7.00 (m, 2H), 7.10-7.35 (m, 4), 7.44 (t, 1H),7.58 (d, 1H), 7.76 (d, 1H), 7.80 (d, 1H), 7.98 (d, 1H), 8.04 (s, 1H),8.40 (d, 1H).

Step 3

Using the procedure of Example 29, Method A, Step 3, the ester of Step 2was converted to the title sodium salt

Anal. calc'd for C₃₃ H₃₄ ClN₂ O₄ SNa·0.5H₂ O: C, 63.70; H, 5.67; N,4.50; S, 5.15; Cl, 5.70; Na, 3.70. Found: C, 63.51; H, 5.78; N, 4.07; S,5.61; Cl, 5.48; Na, 3.60.

EXAMPLE 362-(3-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-3-((3-((2-methyl-2-propyl)amino)-3-oxopropyl)thio)propyl)benzoicacid Step 1 Preparation of methyl2-(3-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-2propenyl)benzoate

Using the procedure of Example 29, Method B, Steps 1-6, the aldehyde ofExample 3, Step 2, was converted to the title product.

¹ H NMR (CD₃ COCD₃) δ (ppm): 3.10-3.35 (m, 4H), 3.72 and 3.88 (m, 5H;cis:trans mixture), 5.70 and 6.42 (m, 2H), 7.05-7.60 (m, 10H), 7.80-8.02(m, 2H), 8.20 (m, 1H).

Step 2

The styrene of Step 1 was converted to the title acid using theprocedure of Example 35.

¹ H NMR (CD₃ COCD₃) δ (ppm): 1.28 (s, 9H), 2.10 (td, 2H), 2.25 (t, 2H),2.50 (m, 2H), 2.90 (m, 2H), 3.15 (t, 2H), 3.32 (t, 2H), 3.86 (t, 1H),6.80 (br s, 1H, NH), 7.00 (m, 1H), 7.10-7.35 (m, 5H), 7.40-7.53 (m, 3H),7.90 (d, 2H), 8.02 (s, 1H), 8.25 (d, 1H).

EXAMPLE 373-(3-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-3-((3-dimethylamino)-3-oxopropyl)thio)propyl)benzoicacid Step 1 Preparation of 3-(1,3-dioxolan-2-yl)benzaldehyde

Ethylene glycol (4.5 mL, 1.05 equiv.), isophthalaldehyde (10.201 g, 76mmoles) and p-toluenesulfonic acid (560 mg) were heated at reflux inbenzene (100 mL) for 8.5 hours. Water was continuously removed from thereaction mixture with a Dean-Stark apparatus. The solvent was thenevaporated and the title compound was purified by flash chromatographyon silica using EtOAc:toluene 2.5:92.5 and 5.95.

¹ H NMR (CDCl₃) δ (ppm): 4.13 (m, 4H), 5.90 (s, 1H), 7.57 (t, 1H), 7.77(d, 1H), 7.91 (d, 1H), 8.03 (s, 1H), 10.05 (s, 1H) ppm.

Step 2 Preparation of methyl 3-(1,3-dioxolan-2-yl)benzoate

Using the procedure of Example 1, Step 4, the aldehyde of Step 1 wasoxidized to the title ester, which was used as such for the next step.

Step 3 Preparation of methyl 3-formylbenzoate

To the ketal of Step 2 (10.046 g, 45.7 mmoles) in THF:MeOH 3:2 (100 mL),10N aqueous HCl (80 mL) was added and the mixture was stirred for 1hour. Addition of 25% aq. NH₄ OAc, extraction with EtOAc, drying overMgSO₄ and flash chromatography of the residue on silica usingEtOAc:toluene 2.5:97.5 yielded the title aldehyde.

¹ H NMR (CDCl₃) δ (ppm): 4.00 (s, 3H), 7.67 (t, 1H), 8.10 (d, 1H), 8.32(d, 1H), 8.54 (s, 1H), 10.08 (s, 1H).

Step 4 Preparation of methyl 3-(2-(trimethylsilyl)oxiranyl)benzoate

Using the procedure described in J. Am. Chem. Soc., 1977, 99, 4536, theproduct of Step 3 was converted to the title epoxysilane. In order toimprove the yield, the anion of chloromethyltrimethylsilane was formedat -78° C. for 1.2 hours and the aldehyde, dissolved in THF and cooledto -78° C., was added to this anion at -100° C.

¹ H NMR (CD₂ Cl₂) δ (ppm): -0.17 and 0.15 (2s, 9H, mixture of cis:transepoxyde), 2.32 and 2.55 (2d, 1H), 3.75 and 4.28 (2d, 1H), 3.90 (s, 3H),7.37-7.60 (m, 2H), 7.90-8.05 (m, 2H).

Step 5 Preparation of methyl 3-(formylmethyl)benzoate

At 0° C., formic acid (6 mL) was added to a solution of the epoxysilaneof Step 4 (605 mg, 2.42 mmoles) in THF:H₂ O 10:1 (6.6 mL) and themixture was stirred at r.t. for 4 hours. The solvents were evaporatedand the product was purified by flash chromatography on silica usingEtOAc:hexane 15:85 and 20:80 sequentially.

¹ H NMR (CDCl₃) δ (ppm): 3.80 (s, 2H), 3.93 (s, 3H), 7.45 (m, 2H), 7.90(s, 1H), 8.00 (d, 1H), 9.80 (s, 1H).

Step 6 Preparation of methyl3-(3-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-2-propenyl)benzoate

The title compound was obtained using the procedure of Example 29,Method B, Steps 4-6, with the following modifications to Step 4: 1.2equiv. of phosphonium salt and 1.0 equiv. of KHMDS were used, and thealdehyde used was that of Example 37, Step 5.

¹ H NMR (CDCl₃) δ (ppm): 3.15 (m, 2H), 3.27 (m, 2H), 3.60 (d, 2H), 3.91(s, 3H), 5.78 and 6.22-6.63 (2m, 2H, cis:trans mixture), 7.05-7.30 (m,5H), 7.30-7.50 (m, 3H), 7.70 (2 d, 1H), 7.83-8.10 (m, 4H).

Step 7

Using the procedure of Example 29, Method A, Step 1 and Step 3, theproduct of Step 6 was converted to the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.10 (m, 2H), 2.37 (m, 2H), 2.48 (t, 2H),2.60 (t, 2H), 2.80 (s, 3H), 2.86 (s, 3H), 3.18 (m, 2H), 3.32 (m, 2H),3.80 (t, 1H), 7.15-7.30 (m, 4H), 7.40 (m, 3H), 7.50 (d, 1H), 7.80-7.92(m, 3H), 8.04 (s, 1H), 8.22 (d, 1H).

EXAMPLE 382-((3-((7-chloro-2-quinolinyl)methoxy)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)benzoicacid Step 1 Preparation of3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-1-(3H)isobenzofuranone

At -100° C., 1.6M BuLi (2.7 mL, 4.32 mmoles) was added dropwise to asuspension of 2-bromobenzoic acid (421 mg, 2.09 mmoles) in THF (8.5 mL)and the mixture was stirred at -78° C. for 2.5 hours. At -100° C., asolution of 3-((7-chloro-2-quinolinyl)methoxy)benzaldehyde (EP 233,763,Example 16, Step 1; 498 mg, 1.67 mmoles) in THF (6 mL) was added and themixture was stirred at -78° C. for 45 min., then at 0° C. for 15 min.AcOH was added at 0° C. and the reaction mixture was poured into 1N HCland stirred overnight. 25% aq. NH₄ OAc was then added and the pH wasadjusted to 5 by addition of 8N KOH. Extraction with EtOAc:THF 1:1,drying over Na₂ SO₄ and flash chromatography of the residue usingEtOAc:toluene 5:95 afforded the title lactone.

¹ H NMR (CD₃ COCD₃) δ (ppm): 5.38 (AB system, 2H), 6.58 (s, 1H), 7.00(d, 1H), 7.10 (m, 2H), 7.30-7.45 (m, 2H), 7.55-7.75 (m, 4H), 7.88 (d,1H), 8.02 (m, 2H), 8.38 (d, 1H).

Step 2 Preparation of2-((3-((7-chloro-2-quinolinyl)methoxy)phenyl)hydroxymethyl)benzoic acid

To the lactone of Step 1 (188 mg, 468 μmoles) in THF:MeOH 1:1 (6 mL),3.3N NaOH (2 mL) was added. The mixture was stirred at r.t. for 3 days.A saturated solution of NH₄ Cl was added and the product was extractedwith EtOAc, dried over Na₂ SO₄ and concentrated. It was used as such forthe next step.

Step 3

Using the procedure of Example 31, Step 2, the hydroxyacid of Step 2 wasconverted to the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.52 (m, 2H), 2.62 (m, 2H), 2.80 (s, 3H),2.90 (s, 3H), 5.37 (s, 2H) 6.62 (s, 1H), 6.94 (d, 1H), 7.10 (d, 1H),7.20-7.35 (m, 3H), 7.43 (t, 1H), 7.60 (dd, 1H), 7.68 (m, 2H), 7.89 (d,1H), 8.00 (d, 1H), 8.05 (s, 1H), 8.38 (d, 1H).

EXAMPLE 392-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-((3-oxo-3-(1-(tricyclo[3.3.1.1³,7]decyl)amino)propyl)thio)propyl)benzoic acid, sodium salt

Using the procedure of Example 35, with the modifications below, thetitle compound was synthesized. The modifications were only in Step 2,where 1) 1-adamantanamine hydrochloride (3 equiv.) was used instead oftert-butylamine, 2) 3 equiv. of Et₃ N were added with the adamantanamineand 3) 3 equiv. of each Et₃ N and 2-chloro-1-methylpyridinium iodidewere used for the formation of the activated ester.

Anal. calc'd for: C₃₉ H₄₀ ClN₂ O₄ SNa·1.5 H₂ O: C, 65.21; H, 6.03; N,3.90; Cl, 4.94; Na, 3.20. Found: C, 65.24; H, 6.16; N, 3.70; Cl, 4.49;Na, 2.94.

EXAMPLE 40 N,N-dimethyl3-((1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-(2-(1H-tetrazol-5-yl)phenyl)propyl)thio)propanamide,sodium salt Step 1 Preparation of2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-2-propenyl)benzonitrile

To the aldehyde (Example 29, Method B, Step 5) (700 mg) were addedformic acid (5 mL), sodium formate (360 mg, 1.8 equiv.) andhydroxylamine hydrochloride (230 mg, 1.15 equiv.). The resulting mixturewas warmed at 95° C. for 1 hr and then allowed to cool to roomtemperature. The reaction was quenched by the addition of saturatedaqueous sodium bicarbonate, extracted with ether and dried with Na₂ SO₄.The residue was purified by flash chromatography using 15% ethyl acetatein toluene to afford the title product.

¹ H NMR (CD₃ COCD₃) δ (ppm): 3.75 (m, 2H), 5.38 and 5.43 (2s, 2H), 5.76and 6.41 to 6.70 (m, 2H, cis:trans mixture), 6.90 to 7.46 (m, 13H).

Step 2 Preparation of N,N-dimethyl3-((1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-(2-cyanophenyl)propyl)thio)propanamide

Using the procedure of Example 29, Method A, Step 1, the cyanostyrene ofStep 1 was converted to the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.04 (q, 2H), 2.41 (m, 2H), 2.55 (m, 2H),2.75 (m, 2H), 2.80 and 2.86 (2s, 6H), 3.96 (t, 1H), 5.40 (s, 2H), 6.95to 8.06 (m, 12H), 8.40 (d, 1H).

Step 3

To the nitrile (Step 2) (300 mg) dissolved in CH₂ Cl₂ (0.1 mL) was addedtributyltin azide (122 mg). The CH₂ Cl₂ was removed by a flow ofnitrogen and the mixture warmed at 120° C. After 8 hrs, additionaltributyltin azide was added (100 mg). After warming 4 hrs, the reactionmixture was purified by flash chromatography (20% acetone in toluenewith 1% of acetic acid) to give the corresponding tetrazole.

To the tetrazole (278 mg) dissolved in ethanol (10 mL) was added sodiumhydroxide 1M (473 μL, 1 equiv.) and the solution was freeze dried togive the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.15 (m, 2H), 2.41 (m, 2H), 2.53 (m, 2H),2.83 and 2.91 (2s, 6H), 3.15 (m, 2H), 3.86 (t, 1H), 5.38 (s, 2H), 6.88to 8.05 (m, 12H), 8.36 (d, 1H).

Anal. calc'd for C₃₁ H₃₀ ClN₆ O₂ SNa·2.5H₂ O: C, 56.92; H, 5.39; Cl,5.42; N, 12.84; S, 4.90; Na, 3.51. Found: C, 56.80; H, 5.43; Cl, 5.33;N, 12.70;, S, 5.42; Na, 3.55.

EXAMPLE 41 N,N-dimethyl3-((1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-(2-((1H-tetrazol-5-yl)methyl)phenyl)propyl)thio)propanamide,sodium salt Step 1 Preparation of2-((3-(3-(2-(bromomethyl)phenyl)-1-propenyl)phenoxy)methyl)-7-chloroquinoline

Using the procedure of Example 29, Method B, Step 2, the benzyl alcoholof Example 29, Method B, Step 4 was converted to the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 3.75 (m, 2H), 4.66 (s, 2H), 5.36 (s, 2H),5.80 and 6.46 to 6.63 (m, 2H, cis:trans mixture) 6.91 to 8.05 (m, 12H),8.36 (d, 1H).

Step 2 Preparation of7-chloro-2-((3-(3-(2-(cyanomethyl)phenyl)-1-propenyl)phenoxy)methyl)quinoline

To the benzyl bromide (Step 1) (930 mg) dissolved in ethanol (13.5 mL)and water (2.7 mL) was added NaCN (611 mg, 6.5 equiv.). The resultingsuspension was stirred at 60° C. for 1 hr and acetone (4 mL) was added.The mixture was warmed at 80° C. for 2 hr then cooled to 40° C. for 18hr. The resulting solution was then poured in an ethyl acetate/25%aqueous ammonium acetate mixture, extracted with ethyl acetate anddried. The residue was purified by flash chromatography using 3% ethylacetate in toluene to give the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 3.63 (m, 2H), 3.96 (m, 2H), 5.35 (m, 2H),5.70 and 6.41 to 6.61 (m, 2H, cis:trans mixture), 6.86 to 8.05 (m, 12H),8.50 (2d, 1H).

Step 3 Preparation of N,N-dimethyl3-((1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-(2-(cyanomethyl)phenyl)propyl)thio)propanamide

Using the procedure of Example 29, Method A, Step 1, the benzyl nitrileof Step 2 was converted to the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.11 (m, 2H), 2.41 (m, 2H), 2.55 (m, 2H),2.75 (m, 2H), 2.83 and 2.90 (2s, 6H), 3.83 (s, 2H), 3.96 (t, 1H), 5.41(s, 2H), 6.96 to 8.06 (m, 12H), 8.41 (d, 1H).

Step 4

Using the procedure of Example 40, Step 3, the benzyl nitrile of Step 3was converted to the title compound (except that the formation of thetetrazole was completed within 4 hrs).

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.10 (m, 2H), 2.45 (m, 2H), 2.60 (m, 2H),2.76 (m, 2H), 2.85 and 2.93 (2s, 6H), 3.95 (t, 1H), 4.08 (s, 2H), 6.91to 8.08 (m, 12H), 8.41 (d, 1H).

Anal. calc'd for C₃₂ H₃₂ ClN₆ O₂ SNa·3H₂ O: C, 56.76; H, 5.66; Cl, 5.24;N, 12.41; S, 4.73; Na, 3.39. Found: C, 56.54; H, 5.63; Cl, 5.74; N,12.14; S, 5.45; Na, 3.38.

EXAMPLE 422-(3-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-((3-dimethylamino-3-oxopropyl)thio)propyl)benzeneaceticacid, sodium salt Step 1 Preparation of methyl2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-((3-dimethylamino-3-oxopropyl)thio)propyl)benzeneacetate

A solution of benzyl nitrile (Example 41, Step 3) (400 mg) dissolved inmethanol (6 mL) saturated with HCl gas was stirred at 60° C. for 5 hrs.The solvent was removed under reduced pressure and flash chromatography(40% ethyl acetate in toluene) of the resulting residue gave the titlecompound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.10 (m, 2H), 2.41 (m, 2H), 2.55 (m, 2H),2.66 (m, 2H), 2.83 and 2.91 (2s, 6H), 3.58 (2s, 5H), 3.96 (t, 1H), 5.36(s, 2H), 6.95 to 8.08 (m, 12H), 8.41 (d, 1H).

Step 2

To the ester (Step 1) (360 mg) dissolved in methanol (20 mL) and water(5 mL) was added K₂ CO₃ (200 mg). After 2 hr at room temperature NaOH10N (500 μL) was added. After a period of 18 hrs the methanol wasremoved at reduced pressure and the resulting residue was partitionedbetween ethyl acetate and water (pH˜5 with acetic acid). The organicphase was collected, dried and evaporated to give the acid.

The acid (280 mg) was dissolved in ethanol and treated with NaOH 1M (484μL, 1 equiv.). The solution was then freeze dried to give the titlecompound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.21 (m, 2H), 2.36 (m, 2H), 2.50 (m, 2H),2.61 (m, 2H), 2.83 and 2.90 (2s, 6H), 3.45 (s, 2H), 2.93 (t, 1H), 5.43(s, 2H), 6.91 to 8.16 (m, 12H), 8.38 (d, 1H).

Anal. calc'd for C₃₂ H₃₂ ClN₂ O₄ SNa·2.3H₂ O: C, 60.00; H, 5.76; Cl,5.53; N, 4.37; S, 5.00. Found: C, 60.02; H, 5.83; Cl, 5.92; N, 4.17; S,5.05.

EXAMPLE 433-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(2-(dimethylaminocarbonyl)phenyl)propyl)thio)propanoicacid, sodium salt Step 1 Preparation of N,N-dimethyl2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-2propenyl)benzamide

To the ester (Example 29, Method B, Step 6) (500 mg) dissolved in CH₂Cl₂ (5 mL) was added a solution of dimethylaluminum dimethylamide (0.8M,7 mL, 5 equiv.) in toluene. The solution was stirred in a sealed tube at60° C. After 36 hrs the reaction mixture was poured in ethyl acetate (50mL), and HCl (10%, 20 mL) was then added at 0° C. After extraction withethyl acetate, drying (Na₂ SO₄) and evaporation, the resulting mixturewas purified by flash chromatography with 25% ethyl acetate in tolueneto give the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.75 and 2.86 (4s, 6H), 3.38 to 3.66 (m,2H), 5.38 (2d, 2H), 5.78 and 6.30 to 6.55 (m, 2H, cis:trans mixture),6.86 to 8.08 (m, 12H), 8.40 (d, 1H).

Step 2

Using the procedure of Example 29, Method A, Step 1, but using methyl3-mercaptopropanoate instead of N,N-dimethyl 3-mercaptopropanamide, thestyrene amide of Step 1 was converted the thioether.

The ester was hydrolyzed using the procedure of Example 42, Step 2 togive the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.10 (m, 2H), 2.20 (m, 2H), 2.36 (m, 2H),2.45 (m, 2H), 2.50 and 2.86 (2s, 6H), 3.76 (t, 1H), 5.33 (s, 2H), 6.83to 7.83 (m, 12H), 8.25 (d, 1H).

Anal. calc'd for C₃₁ H₃₀ ClN₂ O₄ SNa·2.5H₂ O: C, 59.09; H, 5.60; Cl,5.62; N, 4.44; S, 5.08; Na, 3.65. Found: C, 59.54; H, 5.32; Cl, 5.84; N,4.58; S, 5.93; Na, 3.89.

EXAMPLE 44 N,N-dimethyl3-((1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-1-(3-((1H-tetrazol-5-yl)methyl)phenyl)methyl)thio)propanamide,sodium salt Step 1 Preparation of1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-1-(3-(((2-methyl-2-propyl)diphenylsilyloxy)methyl)phenyl)methanol

To the bromide from Example 25, Step 3 (2 g) dissolved in THF (9.7 mL)was added magnesium (128 mg, 1.1 equiv.) followed by few drops of1,2-dibromoethane. The mixture was warmed to 60° C. until most of themagnesium has been consumed. The solution (5.7 mL) was then added to asolution of 3-((7-chloro-2-quinolinyl)methoxy)benzaldehyde (EP 233,763,Example 16, Step 1) (500 mg) in THF (9.7 mL) at 0° C. After 1 hr 25%aqueous ammonium acetate solution was added and the mixture extractedwith ethyl acetate, dried and evaporated. The residue was purified byflash chromatography with 3% ethyl acetate in toluene to yield the titlecompound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 1.04 (s, 9H), 4.75 (s, 2H), 4.86 (d, 1H),5.80 (s, 1H), 6.78 to 8.08 (m, 22H), 8.36 (d, 1H).

Step 2 Preparation of7-chloro-2-((3-((3-(((2-methyl-2-propyl)diphenylsilyloxy)methyl)phenyl)chloromethyl)phenoxy)methyl)quinoline

Using the procedure of Example 26, Step 2, the benzyl alcohol of Step 1was converted to the title compound, which was used as such for the nextstep.

Step 3 Preparation of N,N-dimethyl3-((1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-1-(3-(((2-methyl-2-propyl)diphenylsilyloxy)methyl)phenyl)methyl)thio)propanamide

To the benzyl chloride of Step 2 (1.6 g) dissolved in CH₃ CN (10 mL)were added N,N-dimethyl 3-mercaptopropanamide (500 mL, 1.5 equiv.) andCs₂ CO₃ (1.6 g). The reaction mixture was stirred at 65° C. for 4 hrsthen diluted with ethyl acetate and water, and the organic phase wasdried and evaporated. The crude mixture was purified by flashchromatography with 25% ethyl acetate in toluene to afford the titlecompound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 0.95 (s, 9H), 2.46 (m, 2H), 2.56 (m, 2H),2.78 and 2.86 (2s, 6H), 3.91 (s, 2H), 5.33 (s, 1H), 5.38 (s, 2H), 6.90to 8.08 (m, 22H), 8.36 (d, 1H).

Step 4 Preparation of N,N-dimethyl3-((1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-1-(3-(hydroxymethyl)phenyl)methyl)thio)propanamide

To the silyl ether (Step 3) (1.4 g) in THF (9 mL) at 0° C. was added asolution of n-tetrabutyl-ammonium fluoride 1M in THF (3.6 mL, 2.equiv.). The resulting solution was allowed to warm to room temperaturefor a few hours. Then 25% aqueous ammonium acetate was added and theproduct was extracted with ethyl acetate, dried and evaporated. Theresidue was purified by flash chromatography (50% ethyl acetate intoluene followed by pure acetone) to give the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.50 (m, 2H), 2.60 (m, 2H), 2.83 and 2.91(2s, 6H), 4.16 (t, 1H), 4.56 (d, 2H), 5.35 (s, 1H), 5.43 (s, 2H), 6.91to 8.08 (m, 12H), 8.40 (d, 1H).

Step 5 Preparation of N,N-dimethyl3-((1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-1-(3-(cyanomethyl)phenyl)methyl)thio)propanamide

To the alcohol (Step 4) (549 mg) in CH₂ Cl₂ (6 mL) at -78° C. were addedtriethylamine (293 μL, 2 equiv.) and methanesulfonyl chloride (122 μL,1.5 equiv.). Then the mixture was allowed to warm to -10° C. and 25%ammonium acetate was added, the mixture was extracted with ethylacetate, dried and evaporated. The crude mixture was purified by flashchromatography (20% acetone in ethyl acetate) to give the mesylate.

To the mesylate (600 mg) dissolved in DMSO (2.4 mL) at r.t. was addedNaCN (240 mg). Then after 4 hr the DMSO was evaporated and the crudemixture was purified by flash chromatography (50% ethyl acetate intoluene) to afford the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.55 (m, 2H), 2.61 (m, 2H), 2.83 and 2.91(2s, 6H), 3.93 (s, 2H), 5.41 (s, 2H), 5.43 (s, 1H), 6.91 to 8.05 (m,12H), 8.38 (d, 1H).

Step 6

Using the procedure of Example 40, Step 3, the benzyl nitrile of Step 5was converted to the title compound (except that the formation of thetetrazole was completed within 4 hrs).

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.46 (m, 2H), 2.55 (m, 2H), 2.76 and 2.80(2s, 6H), 4.05 (s, 2H), 5.25 (s, 1H), 5.28 (s, 2H), 6.83 to 8.00 (m,12H), 8.33 (d, 1H).

Anal. calc'd for C₃₀ H₂₈ ClN₆ OSNa·6H₂ O: C, 52.44; H, 5.87; Cl, 5.16;N, 12.23; S, 4.67; Na, 3.35 Found: C, 52.52; H, 5.53; Cl, 5.33; N,12.14; S, 5.20; Na, 3.71

EXAMPLE 453-(((3-Carboxyphenyl)thio)(3-((7-chloro-2-quinolinyl)methoxy)phenyl)methyl)benzoicacid, disodium salt Step 1

Preparation ofmethyl13-(((3-(methoxycarbonyl)phenyl)thio)(3-((7-chloro-2-quinolinyl)methoxy)phenyl)methyl)benzoate

To a r.t. solution of the alcohol of Example 9, Step 1 (445 mg) in CCl₄(10 c.c.) and CH₂ Cl₂ (30 c.c.) was added tri-n-octylphosphine (1.3 g)and the mixture reacted for 1.5 hr. The reaction mixture was filteredthrough a plug of SiO₂ and the intermediate chloride isolated afterremoval of the solvent. This chloride (155 mg) was taken in CH₃ CN (5c.c.), methyl 3-mercaptobenzoate (84 mg) was added followed by drycesium carbonate (163 mg) and the mixture was heated at 75° C. for 0.5hr. After cooling, ethyl acetate (10 c.c.) was added and the organiclayer was washed with 25% NH₄ OAc (5 c.c), brine, dried with MgSO₄ andthe solvent removed in vacuo to yield the title compound afterpurification by chromatography.

¹ H NMR (CDCl₃) δ (ppm): 3.70-3.90 (2s, 6H), 5.20 (s, 2H), 5.45 (s, 1H),6.70-8.05 (m, 17H).

Step 2

To a 0° C. solution of the ester of Step 1 (144 mg) in tetrahydrofuran(4 c.c.) and methanol (1 c.c.) was added 2N NaOH (370 μL) and themixture was kept at 0° C. for 2 days. 25% NH₄ OAc (5 c.c.) and aceticacid (3 drops) were added and the product was extracted in ethyl acetate(3×5 c.c). The organic layer was washed with brine and the solvents wereremoved in vacuo. The residue (126 mg) was taken in H₂ O (2 c.c.)containing 2N NaOH (228 μL) and the solution was freeze dried to yieldthe title compound.

¹ H NMR (DMSO-d₆ containing 10% CD₃ COCD₃) δ (ppm): 5.30 (s, 2H), 5.80(s, 1H), 6.85-8.50 (m, 17H).

EXAMPLE 463-(((3-((7-Chloro-2-quinolinyl)methoxy)phenyl)(3-(2-dimethylamino-2-oxoethyl)phenyl)methyl)thio)propanoicacid, sodium salt Step 1 Methyl3-((3-((7-chloro-2-quinolinyl)methoxy)phenyl)formyl)phenylacetate

The secondary alcohol of the product of Example 44, Step 1, was oxidizedto the ketone as in Example 29, Method B, Step 5. The benzylic alcoholwas then deprotected (Example 44, Step 4) and the nitrile was formed(Example 44, Step 5). Treatment of this nitrile with HCl in MeOH in asealed tube for 6 h at 65° C. yielded the title methyl ester.

Step 2

The ester was reacted with Me₂ NAlMe₂ (Example 366, Step 10) to affordthe dimethylamide. Reduction of the ketone with NaBH₄ (Example 29,Method B, Step 1) gave a benzylic alcohol, which was reacted withmethanesulfonyl chloride and triethylamine in dichloromethane at -40°C., then at r.t. by 3 h to yield the chloride. The chloride was thensubstituted by methyl 3-mercaptopropanoate in the presence of Cs₂ CO₃(Example 44, Step 3). Finally, hydrolysis of the ester using theprocedure of Example 42, Step 2 afforded the title compound.

Anal. calcd for C₃₀ H₂₈ ClN₂ SO₄ Na·H₂ O: C, 61.12; H, 5.09; N, 4.75.Found: C, 60.99; H, 4.96; N, 4.73.

Example 1093-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(4-chloro-2-(dimethylaminocarbonyl)phenyl)propyl)thio)propanoicacid Step 1 1-Acetoxy-7-chloro-3,4-dihydronaphthalene

To a solution of 7-chlorotetralone (Can. Pat. 974997) (100 g) inisopropenyl acetate (400 mL) was added conc. H₂ SO₄ (1 mL) and themixture was refluxed for 16 hrs then cooled to room temperature andevaporated to dryness under reduced pressure. The residue was passedthrough a plug made of celite (100 g) and NaHCO₃ (100 g) using EtOAc;the filtrate was concentrated in vacuo and passed through a plug of SiO₂(12 cm×12 cm) using 30% EtOAc in hexanes, and the fractions containingthe product combined and evaporated to dryness to yield the titlecompound as an oil (114 g, 93%), homogeneous by ¹ H NMR.

¹ H NMR (CD₃ COCD₃)δ: 2.30 (3H, s), 2.35-2.45 (2H, m), 2.75-2.85 (2H,m), 5.80 (1H, t), 7.1 (1h, br s*), 7.2 (2H, br s). *br s≈broad singlet

Step 2 2-(3-Oxopropyl)-5-chlorobenzoic acid

To a cold solution (-78° C.) of the crude enol acetate from Step 1 (57g) in CH₂ Cl₂ (250 mL) was added MeOH (50 mL) and the solution treatedwith an ozone/oxygen mixture from a Welsbach T-23 ozonator at -78° untila light blue color persisted (or until TLC showed no more startingmaterial). Excess ozone was then blown away with N₂ and a CH₂ Cl₂ (200mL) solution of PPh₃ (80 g) was added at -78° and kept at -78° for 2hrs; the mixture was then allowed to warm to r.t. and the solvents wereremoved on a rotavap. The residue was divided in two and each portiondissolved in THF (500 mL)-MeOH (150 mL) and then treated at 0° C. with1N HCl (150 mL) for 4 hrs. An acid/base work-up using 10% NaHCO₃ and Et₂O yielded, after acidification (6N HCl) at 0° C. and extraction intoEtOAc, the title compound as a semi-solid residue (39.3 g, 67% combinedyield).

¹ H NMR (CD₃ COCD₃)δ: 2.80-2.90 (2H, t), 3.25-3.35 (2H, t), 7.45-7.65(2H, m), 7.95 (1H, d), 9.80 (1H, CHO, s).

Step 3 3-(t-Butyldiphenylsiloxy)bromobenzene

To a solution of 3-bromophenol (377 g) in CH₂ Cl₂ (2.6 L) was added Et₃N (424 mL) and t-butyldiphenylsilyl chloride (611 g). The reaction wasstirred at r.t. for 3 days, poured onto 4 L of aqueous NH₄ OAc (25%),extracted with Et₂ O, dried and evaporated. Flash chromatography of theresidue using 5% EtOAc/hexane afforded 716 g (80%) of the titlecompound.

¹ H NMR (CDCl₃)δ: 1.09 (9H, s), 6.59 (1H, d), 6.90 (1H, t), 7.00 (2H,m), 7.33-7.48 (6H, m), 7.71 (4H, m).

Step 45-Chloro-2-(3-hydroxy-3-(3-t-butyldiphenylsiloxy)phenyl)propyl)benzoicacid

To a suspension of Mg (19.9 g, 0.77 mol) in THF (800 mL) was added thebromide from Step 3 (26 g, 64 mmol) and 1,2-dibromoethane (1 mL). Themixture was warmed to initiate the reaction. The remaining bromide (239g, 0.58 mol) in THF (250 mL) was added dropwise over 1 h. The reactionwas stirred overnight at r.t. The Grignard solution was decanted, usinga canula, from the remaining Mg and used as such.

To the Grignard solution at 0°-5° was added dropwise the aldehyde fromStep 2 (45 g, 0.26 mol) in THF (250 mL). After 1 hour the reaction waspoured into NH₄ Cl(250 g in 2 L H₂ O) and extracted with EtOAc, dried(Na₂ SO₄) and evaporated. Flash chromatography of the residue, using 20%EtOAc in hexane to 40% EtOAc-5% HOAc in hexane, afforded 120 g (92%) ofthe title compound.

¹ H NMR (CD₃ COCD₃)δ: 1.05 (9H, s), 1.80 (2H, q), 2.95 (2H, m), 4.95(1H, t), 6.60 (1H, dd), 6.90 (2H, m), 7.05 (1H, t), 7.20-7.40 (1H, m),7.35-7.50 (7H, m), 7.70-7.80 (4H, m), 7.90 (1H, d).

Step 58-Chloro-4,5-dihydro-3-(3-(t-butyldiphenylsiloxy))phenyl-2-benzoxepin-1(3H)-one

To the hydroxyacid of Step 4 (28 g, 51.4 mmol) and triethylamine (14 mL,100 mmol) in 250 mL of CH₂ Cl₂ :CH₃ CN 4:1 at 0° C.,2-chloro-1-methylpyridinium iodide (26.0 g, 100 mmol) was added and theresulting mixture was stirred at 0° C. for 2.5 h. 25% aq NH₄ OAc wasthen added and the title lactone was extracted with EtOAc, dried overNa₂ SO₄ and purified to yield 24.00 g (89%) by flash chromatography onsilica with EtOAc:hexane 15:85.

Step 6 8-Chloro-4,5-dihydro-3-(3-hydroxyphenyl)-2-benzoxepin-1(3H)-one

At 0° C., 1.0M Bu₄ NF (tetrabutylammonium fluoride, 55 mL) was added toa solution of the lactone of Step 5 (24.00 g, 45.5 mmol) and HOAc (7.0mL, 122 mmol) in 250 mL of anhydrous THF and the resulting mixture wasstirred at 0° C. for 2 h. 25% aq NH₄ OAc was then added and the titlephenol was extracted with EtOAc, dried over Na₂ SO₄ and purified toyield 10.5 g, (80%) by flash chromatography on silica with EtOAc:hexanes3:10.

Step 7 8-Chloro-3-(3-((7-chloro-quinolinyl)methoxy)phenyl)-4,5-dihydro-2-benzoxepin-1-(3H)-one

Using the procedure of Example 25, Step 10, the product of Step 6 wasconverted to the title compound. Yield: 90%.

¹ H NMR (CD₃ COCD₃) δ: 2.35 (2H, m), 3.00 (2H, m), 5.15 (1H, dd), 5.47(2H, s), 7.00 (2H, m), 7.23 (1H, d), 7.29 (1H, t), 7.40 (1H, d), 7.60(3H, m), 7.75 (1H, d), 8.00 (2H, m), 8.40 (1H, d).

Step 8 N,N-Dimethyl5-chloro-2-(3-hydroxy-3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)propyl)benzamide

To a solution of the lactone (46.4 g, 100 mmol) from Step 7 in toluene(250 mL) at 0° C. was added 0.95M Me₂ AlNMe₂ in toluene (210 mL, 200mmol) and the mixture was warmed up to 60° C. for 1 h. It was thencooled, poured slowly onto HCl (800 mL). EtOAc (300 mL) was added andthe mixture was stirred until a clean separation of the layers wasobtained. The pH of the aq phase was adjusted to 6 with NaOH and the aqlayer was extracted twice again with EtOAc. The organic layer was washedwith brine and the solvents removed to yield the pure title compoundwhich was used as such in the next step.

¹ H NMR (CD₃ COCD₃) δ: 1.8-2.0 (2H, m), 2.5-2.75 (2H, m), 2.8 (3H, s),3.0 (3H, s), 4.55 (1H, bt), 5.35-5.45 (2H, bs), 6.9-8.9 (12H, m).

Step 9N,N-Dimethyl-5-chloro-2-(3-methanesulfonyloxy-3-((7-chloro-2-quinolinyl)methoxy)phenyl)propyl)benzamide

To a solution of 11.2 g (22 mmol) of amide from Step 8 and 5.1 mL (37mmol) of triethylamine in 200 mL of CH₂ Cl₂ was added dropwise 2.2 mL(28 mmol) of methanesulfonyl chloride at -40°. The reaction was stirredat this temperature for 15 min., warmed up to -10° within 30 min. andstirred at -10° for 1 h. The reaction was quenched by pouring intoice-aq. NaHCO₃ and extracted twice with CH₂ Cl₂. After removal of thesolvent the crude title compound was used as such for the next step.

Step 10 Methyl3-((1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-(4-chloro-2-(dimethylaminocarbonyl)phenyl)propyl)thio)propanoate

The crude mesylate (ca. 22 mmol) from Step 9 was dissolved in 300 mL ofacetonitrile. To the solution, which was degassed by bubbling argonthrough for a few min., was added 6.1 mL (55 mmol) of methyl3-mercaptopropanoate, followed by 24.3 g (75 mmol) of Cs₂ CO₃. Themixture was stirred at r.t. for 1 h. The solid was filtered, thereaction was diluted with CH₂ Cl₂ and washed twice with sat. NH₄ Clsolution. Chromatographic purification with toluene:EtOAc 4:1 afforded9.7 of the title compound (72%).

¹ H NMR (CD₃ COCD₃) δ: 2.0-2.2 (2H, m), 2.3-3.0 (12H, m), 3.55 (3H, s),3.8-3.95 (1H, t), 5.5 (2H, s), 6.9-8.4 (12H, m).

Step 11

To a solution of 9.0 g of ester from Step 10 in 200 mL of MeOH, 50 mL ofaq K₂ CO₃ solution (1M) was added. The mixture was stirred undernitrogen at r.t. for 15 hrs. The MeOH was partially evaporated, and thereaction was neutralized by addition of 5 mL of HOAc. The product wasthen partitioned between aq NH₄ Cl and EtOAc containing 2% HOAc. Thecrude product was purified on silica gel to give 7.6 g of the title acid(87%).

¹ H NMR (CD₃ COCD₃) δ: 2.0-3.0 (8H, m), 2.75 (3H, s), 2.95 (3H, s), 3.95(1H, t), 5.45 (2H, s), 6.95-8.05 (11H, m), 8.4 (1H, d).

Anal. calcd for C₃₁ H₂₉ Cl₂ N₂ O₄ SNa·H₂ O: C, 58.40; H, 4.90; N, 4.39.Found: C, 58.40; H, 4.95; N, 4.41.

Step 12

To a solution of the free acid in EtOH, 1 equiv. of NaOH was added. Themixture was evaporated and the residue was dissolved in H₂ O and freezedried to yield the sodium salt of the title compound.

EXAMPLE 110 N,N-Dimethyl2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-((2-(1H-tetrazol-5-yl)ethyl)thio)propyl)benzamide,sodium salt

Using the method of Example 29, Method A, Step 1,3-mercaptopropanoicacid was added to Styrene 1. The acid was converted to the amide usingthe procedure of Example 35, Step 2, but replacing tert-butylamine byammonia. This amide was dehydrated to the nitrile with trifluoroaceticanhydride (1.1 equiv) and pyridine (6 equiv) in THF (concentration 0.1M)at -10° C. for 30 min. Finally, the title compound was obtained bytreatment with Bu₃ SnN₃ as in Example 40, Step 3.

Anal. calcd for C₃₁ H₃₀ ClN₆ O₂ SNa·2.2H₂ O: C, 57.39; H, 5.30; N,12.93. Found: C, 57.45; H, 4.92; N, 12.60.

EXAMPLE 111 N,N-Dimethyl2-(3-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-3-((2-(1H-tetrazol-5-yl)propyl)thio)propyl)benzamide,sodium salt

Using the procedure of Example 110, but replacing 3-mercaptopropanoicacid by Thiol 5 and starting from Styrene 2, the title product wasobtained.

Anal. Calcd for C₃₃ H₃₄ ClN₆ O₂ SNa·2.5H₂ O: C, 59.49; H, 5.90; N,12.61. Found: C, 59.22; H, 5.55; N, 12.56.

EXAMPLE 1133-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(2-(dimethylaminocarbonyl)phenyl)propyl)thio)-2-ethylpropanoicacid, sodium salt Step 1 Ethyl 3-(acetylthio)-2-ethylpropanoate

Ethyl 2-ethyl-2-propenoate (Arch. Pharm., 313, 846 (1980)) (5 g, 39mmol) was diluted with 5.6 mL (78 mmol) of thiolacetic acid and stirredat 65° C. for 36 h. The mixture was then diluted with Et₂ O, washed withwater, and the organic phase was dried with Na₂ SO₄. Evaporation todryness yielded the title material as an orange oil which was used assuch for the next step.

¹ H NMR (CDCl₃) δ: 0.96 (3H, t), 1.28 (3H, t), 1.70 (3H, m), 2.35 (3H,s), 3.10 (2H, m), 4.18 (2H, q).

Step 2 Ethyl 2-ethyl-3-mercaptopropanoate

To a solution of the thioester of Step 1 (5.00 g, 24.5 mmol) in MeOH (15mL) at 0° C., under nitrogen, was added K₂ CO₃ (9.67 g, 73.5 mmol). Theresulting mixture was stirred at 0° C. for a half hour, and then HOAc(8.82 g, 147 mmol) and 25% aq NH₄ OAc were added. The title thiol wasextracted with EtOAc, dried over Na₂ SO₄ and purified by distillation ona Kugelrohr apparatus (200° C./760 mm Hg). Yield: 1.700 g (45%).

¹ H NMR (CD₃ COCD₃) δ: 0.86 (3H, t), 1.25 (3H, t), 1.65 (2H, quintet),1.78 (1H, t), 2.45 (1H, quintet) 2.68 (2H, m), 4.15 (2H, q).

Step 3

Using the procedure of Example 43, but replacing methyl3-mercaptopropanoate by the thiol of Step 2 in Step 2, the titlecompound was prepared.

Anal. calcd for C₃₃ H₃₄ ClN₂ O₄ SNa: C, 64.63; H, 5.58; N, 4.56. Found:C, 64.48; H, 5.45; N, 4.39.

EXAMPLE 1513-((1-(3-(2-(7-Chloro-2-quinolinyl)ethyl)phenyl)-3-(2-(1H-tetrazol-5-yl)phenyl)propyl)thio)-2-ethylpropanoic,disodium salt

The title compound was obtained from the acid of Example 343 using theprocedure of Example 40, Step 3.

Anal. calcd for C₃₂ H₃₂ ClN₅ O₂ SNa₂ : C, 57.80; H, 5.04; N, 10.37.Found: C, 57.86; H, 4.86; N, 10.54.

EXAMPLE 1523-((1-(3-(2-(7-Chloro-2-quinolinyl)ethyl)phenyl)-3-(2-((4-methylphenylsulfonylaminocarbonyl)phenyl)propyl)thio)-2-ethylpropanoicacid, monosodium salt Step 12-(3-(3-(2-(7-Chloro-2-quinolinyl)ethyl)phenyl)-3-((3-ethoxy-2-ethyl-3-oxopropyl)thio)-propyl)benzoicacid

The ester of Example 36, Step 1, was hydrolyzed to the acid using theprocedure of Example 29, Method A, Step 3. Ethyl2-ethyl-3-mercaptopropanoate (Example 113, Step 2) was then added tothis styrene using the procedure of Example 29, Method A, Step 1, toyield the title compound.

¹ H NMR (CD₃ COCD₃) δ: 0.78 (3H, 2q, mixture of diastereoisomers), 1.20(3H, q), 1.52 (2H, m), 2.14 (2H, m), 2.2-2.6 (3H, m), 2.92 (2H, m), 3.2(2H, m), 3.35 (2H, m), 3.87 (1H, q), 4.10 (2H, 2q), 7.0-7.55 (9H, m),7.91 (2H, d), 8.03 (1H, s), 8.28 (1H, d).

Step 2 Ethyl3-((1-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-3-(2-((4-methylphenylsulfonyl)aminocarbonyl)phenyl)propyl)thio)-2-ethylpropanoate

The acid of Step 1 (645 mg, 1.4 mmol) was dissolved in CH₂ Cl₂ (50 mL)under a nitrogen atmosphere and1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (340 mg,1.8 mmol), p-toluenesulfonamide (260 mg, 1.5 mmol) and4-dimethylaminopyridine (220 mg, 1.8 mmol) were added. The reactionmixture was stirred for 4 h at room temperature before pouring it into1N HCl. Extraction with EtOAc and CH₂ Cl₂, drying over anhydrous MgSO₄and evaporation in vacuo gave the crude title product (900 mg), whichwas used as such for the next step (hydrolysis).

When the reaction was performed on a smaller scale, the title compoundwas purified by preparative thin layer chromatography eluting with anEtOAc:hexane:MeOH:HOAc (20:70:10:1) mixture.

¹ H NMR (CD₃ COCD₃) δ: 0.78 (3H, 2t, a mixture of diastereoisomers) 1.20(3H, 2t), 1.48 (2H, m), 1.86 (2H, m), 2.2-2.6 (5H, m), 2.46 (3H, s),2.90 (1H, NH, br s), 3.15-3.35 (4H, m), 3.6 (1H, q), 4.1 (2H, dq),7.0-7.55 (13H, m), 7.88 (1H, d), 7.96 (1H, d), 7.98 (1H, s), 8.20 (1H,d).

Step 3

Using the procedure of Example 29, Method A, Step 3, but using 2equivalents of KOH instead of 10 equiv. of NaOH, the ester of Step 2 washydrolyzed to the acid which was purified by flash chromatography(toluene:acetone:methanol) followed by reversed phase chromatography(Delta prep column, 65% methanol in aqueous phosphate buffer at pH:7.0).It was then converted to the title compound using the procedure ofexample 14, Step 2, except that only on equiv. of NaOH was used.

¹ H NMR of the acid (CD₃ COCD₃) δ: 0.82 (3H, dt), 1.53 (2H, m), 1.87(2H, m), 2.25-2.60 (5H, m), 2.43 (3H, s), 2.90 (1H, NH, br s), 3.15-3.35(4H, m) 3.61 (1H, m), 7.05-7.55 (13H, m), 7.90 (1H, d), 7.96 (1H, d),7.98 (1H, s), 8.21 (1H, d).

EXAMPLE 1553-((1-(3-(2-(7-Chloro-2-quinolinyl)ethyl)phenyl)-3-(2-(N-methyl*-1H-tetrazol-5-yl)phenyl)propyl)thio)-2-ethylpropanoicacid, disodium salt

The acid-tetrazole of Example 151 was treated with diazomethane inmethanol to afford an ester-N-methyltetrazole. Then, the ester washydrolyzed, as in Example 152, Step 3, to yield the title sodium salt.

¹ H NMR of the acid (CD₃ COCD₃) δ: 0.7-0.9 (3H, m), 1.4-1.6 (2H, m),1.9-2.1 (2H, m), 2.2-2.7 (3H, m), 2.8 (1H, m), 2.95 (1H, m), 3.2-3.45(4H, m), 3.9 (1H, t), 4.4 (3H, s), 7.2-7.5 (9H, m), 7.8 (1H, d), 7.9(1H, d), 8.0 (1H, d), 8.15 (1H, d).

EXAMPLES 160 AND 354

Using the procedure of Example 35, but replacing 3-mercaptopropanoicacid by Thiol 13 and tertbutylamine by dimethylamine and ammoniarespectively, the following compounds were obtained.

EXAMPLE 1602-(3-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-((2-ethyl-3-(dimethylamino)-3-oxopropyl)thio)propyl)benzoicacid, sodium salt

Anal. calcd for C₃₃ H₃₄ ClN₂ O₄ SNa·3.7H₂ O: C, 58.30; H, 6.14; N, 4.12.Found: C, 58.30; H, 6.10; N, 4.07.

EXAMPLE 3542-(3-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-((3-amino-2-ethyl-3-oxopropyl)thio)propyl)benzoicacid, sodium salt

Anal. calcd for C₃₁ H₃₀ ClN₂ O₄ SNa·0.5H₂ O: C, 62.67; H, 5.26; N, 4.72.Found: C, 62.97; H, 5.41; N, 4.66.

EXAMPLE 1783-((1-(3-(2-(7-Chloro-2-quinolinyl)ethyl)phenyl)-3-(2-((ethoxycarbonyl)amino)phenyl)propyl)thio)-2-ethylpropanoicacid, sodium salt Step 1 Ethyl3-((1-(3-(2-(7-Chloro-2-quinolinyl)ethyl)phenyl)-3-(2-((ethoxycarbonyl)amino)phenyl)propyl)thio)-2-ethylpropanoate

To the acid of Example 152, Step 1, (650 mg, 1.1 mmol) dissolved intoluene (30 mL) were added triethylamine (173 μl, 1.24 mmol) anddiphenylphosphoryl azide (372 mg, 1.35 mmol). The reaction mixture washeated 30 minutes at 95° C. before adding EtOH (300 μl). After 14 h ofheating, the solution was concentrated in vacuo. Et₂ O and EtOAc wereadded and the organic phase was washed successively with saturatedaqueous NH₄ Cl, NaHCO₃ and with brine. Drying over MgSO₄ followed byevaporation of the solvents in vacuo gave the crude product which waspurified by flash chromatography (8 to 15% acetone in toluene) to give391 mg of the title compound.

¹ H NMR (CD₃ COCD₃) δ: 0.78 (3H, 2t, a mixture of diastereoisomers) 1.22(3H, t), 1.24 (3H, t), 1.50 (2H, m), 2.0-2.75 (8H, m), 3.20 (2H, m),3.30 (2H, m), 3.81 (1H, m), 4.10 (4H, 2q), 7.05-7.30 (6H, m), 7.41 (1H,d), 7.52 (2H, m), 7.72 (1H, br s), 7.88 (1H, d), 7.96 (1H, s), 8.20 (1H,d).

Step 2

Using the procedure of Example 152, Step 3, the title sodium salt wasobtained.

Anal. calcd for C₃₄ H₃₆ ClN₂ O₄ SNa·H₂ O: C, 63.30; H, 5.94; N, 4.34.Found: C, 63.30; H, 5.84; N, 4.24.

EXAMPLE 2283-(((3-((7-Chloro-2-quinolinyl)methoxy)phenyl)(((2-(dimethylaminocarbonyl)phenyl)methyl)thio)methyl)thio)propanoicacid, sodium salt

Using the procedure of Example 14, Step 1, but replacing methyl3-mercaptobenzoate by a 1:1 mixture of methyl 3-mercaptopropanoate and2-(mercaptomethyl) benzoic acid, a mixed dithioacetal was formed. Theacid was then reacted with 1.1 equiv. of 1,1'-carbonyldiimidazole atr.t. in CH₂ Cl₂ or THF for an hour, then with dimethylamine at r.t. foran hour to give the dimethylamide. Finally, hydrolysis of the ester asin Example 14, Step 2, afforded the title compound.

Anal. calcd for C₃₀ H₂₈ ClN₂ O₄ S₂ Na·H₂ O: C, 58.01; H, 4.87; N, 4.51.Found: C, 57.73; H, 4.82; N, 4.73.

EXAMPLE 2293-((3-(2-(Aminocarbonyl)phenyl)-1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)propyl)thio)-2-methoxypropanoicacid, sodium salt Step 1 Methyl 2-methoxy-2-propenoate

The dimethyl acetal of methyl pyruvate was prepared using methylpyruvate, trimethyl orthoformate, methanol and p-toluenesulfonic acidaccording to the method of Wermuth (Bull. Chem. Soc. Jp., 2987 (1970)).Methyl pyruvate dimethylacetal (50 g) p-toluenesulfonic acid (1.34 g)and hydroquinone (1.90 g) were heated in an oil bath (≈150° C.) andmethanol was allowed to distill off slowly (≈10 mL). The residue wasthen distilled to afford 32 g (81%) of the title ester; bp ≈50° C./20 mmHg.

¹ H NMR (CDCl₃)δ: 3.67 (3H, s), 3.82 (3H, s), 4.65 (1H, d, J=2 Hz), 5.48(1H, d, J=2 Hz).

Step 2 Methyl 3-(benzylthio)-2-methyoxypropanoate

To a solution of the propenoate of Step 1 (26.93 g, 0.23 mol) in THF (20mL) at 0° C. was added benzyl mercaptan (23.0 mL, 0.23 mol) followed by1M THF solution of Bu₄ NF (20 mL). The mixture was stirred at r.t. for 1h. The reaction was poured into H₂ O and extracted with EtOAc, washedwith brine, dried and concentrated to yield 24.89 g (48%) of the titlecompound; b.p. 115°-130° C./1 mm Hg.

¹ H NMR (CDCl₃)δ: 2.76 (2H, m), 3.43 (3H, s), 3.78 (3H, s), 3.82 (2H,s), 3.96 (1H, dd), 7.34 (5H, m).

Step 3 3-(Benzylthio)-2-methoxypropanoic acid

To a solution of the ester (210 mg, 0.875 mmol) of Step 2 in MeOH:H₂ O5:1 (6 mL) was added K₂ CO₃ (210 mg). After 18 h, the reaction wasquenched by the addition of 25% aq NH₄ OAc. After acidification to pH 4with 10% HCl, the product was extracted with EtOAc. The organic phasewas dried over Na₂ SO₄ and evaporated to provide 180 mg, (91%) of thetitle compound.

¹ H NMR (CD₃ COCD₃)δ: 2.73 (2H, m), 3.36 (3H, s), 3.80 (2H, s), 3.95(1H, q), 7.16-7.36 (5H, m).

Step 4 3-Mercapto-2-methoxypropanoic acid

The acid of Step 3 (1.3 g, 5.7 mmol) was dissolved in liquid ammonia at-30° C. and small pieces of Na (469 mg, 20.4 mmol) were added untilobtention of a persistant blue coloration. After 20 min, the ammonia wasremoved by a flow of N₂ and H₂ O (20 mL) and 10% HCl were added untilobtention of pH ≈3.5. The thiol was then extracted with EtOAc, driedover Na₂ SO₄ and evaporated to provide 700 mg (89%) of title material.

¹ H NMR (CD₃ COCD₃)δ: 1.88 (1H, t), 2.80 (2H, m), 3.36 (3H, s), 3.86(1H, t).

Step 5 Methyl 3-mercapto-2-methoxypropanoate

To an ethereal solution of the acid of Step 4 was added CH₂ N₂ at 0° C.The organic solvent was removed under reduced pressure to give the titlecompound.

¹ H NMR (CD₃ COCD₃)δ: 1.93 (1H, t), 2.83 (2H, m), 3.40 (3H, s), 3.73(3H, s), 3.91 (1H, t).

Step 64,5-Dihydro-3-(3-(diphenyl(2-methyl-2-propyl)siloxy)phenyl-2-benzoxepin-1(3H)-one

To 2-(3-hydroxy-3-(3-(tert-butyldiphenylsiloxy)phenyl)propyl)benzoicacid (prepared from α-tetralone as in Example 366, Step 1-4) (25.58 g,50.09 mmol) and triethylamine (22 mL, 158 mmol) in 250 mL of CH₂ Cl₂:CH₃ CN 4:1 at 0° C., 2-chloro-1-methylpyridinium iodide (20.35 g, 79.7mmol) was added and the resulting mixture was stirred at 0° C. for 2.5h. 25% aq NH₄ OAc was then added and the title lactone was extractedwith EtOAc, dried over Na₂ SO₄ and purified by flash chromatography onsilica with EtOAc:hexane 10:90 and 15:85. Yield: 23.00 g, 93%.

Step 7 4,5-Dihydro-3-(3-hydroxyphenyl)-2-benzoxepin-1(3H)-one

At 0° C., 1.0M Bu₄ NF (tetrabutylammonium fluoride, 60 mL) was added toa solution of the lactone of Step 6 (23.00 g, 46.7 mmol) and HOAc (7.0mL, 122 mmol) in 250 mL of anhydrous THF and the resulting mixture wasstirred at 0° C. for 2 h. 25% aq NH₄ OAc was then added and the titlephenol was extracted with EtOAc, dried over Na₂ SO₄ and purified byflash chromatography on silica with EtOAc:toluene 10:90 and 15:85.Yield: 11.45 g, (96%).

Step 83-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-4,5-dihydro-2-benzoxepin-1(3H)-one

Using the procedure of Example 25, Step 10, the product of Step 7 wasconverted to the title compound. Yield: 90%.

¹ H NMR (CD₃ COCD₃ -CD₃ SOCD₃)δ: 2.16-2.45 (2H, m), 2.86-3.10 (2H, m),5.11 (1H, dd), 5.38 (2H, s), 7.01-7.12 (2H, m), 7.24 (1H, br s), 7.30(1H, dd), 7.39-7.50 (2H, m), 7.57-7.70 (3H, m), 7.74 (1H, d), 8.04 (1H,s), 8.07 (1H, d), 8.47 (1H, d).

Step 92-(3-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-((2,3-dimethoxy-3-oxopropyl)thio)propyl)benzoicacid

To the lactone of Step 8 (500 mg, 1.20 mmol) and the thiol of Step 5(270 mg, 1.80 mmol) in 1,2-dichloroethane (12 mL) at 0° C. was added BF₃·Et₂ ⁰ (920 mL, 7.20 mmol). The temperature was allowed to warm to roomtemperature to give a suspension. The mixture was then cooled to 0° C.followed by the addition of trifluoroacetic acid (1 mL). After 15 min,the ice bath was removed and the mixture was stirred until TLC showedcompletion (EtOAc:Hexane 1:1). At that time, the reaction was quenchedby the addition of 25% aq NH₄ OAc at 0° C. The desired product wasextracted with EtOAc, dried over Na₂ SO₄ and purified by flashchromatography on silica using acetone:toluene 20:80 to yield 630 mg(84%) of title material.

¹ H NMR (CD₃ COCD₃)δ: 2.11 (2H, quintet), 2.56 (2H, m), 2.75-3.06 (2H,m), 3.23 and 3.28 (3H, 2s, mixture of diasteromers), 3.64 (3H, 2s), 3.73(1H, m), 3.94 (1H, m), 5.38 (2H, s), 6.94 (1H, m), 7.11-7.28 (6H, m),7.39 (1H, m), 7.56 (1H, dd), 7.73 (1H, d), 7.83-8.04 (2H, m), 8.30 (1H,d).

Step 10

Using the procedure of Example 35, Step 2, but replacing tert-butylamineby ammonia, the acid of Step 9 was converted to the amide. The esterfunction was then hydrolyzed, using the procedure of Example 42, Step 2,to give the title sodium salt.

Anal. calcd for C₃₀ H₂₈ ClN₂ O₅ SNa·1.5H₂ O: C, 58.68; H, 5.09; N, 4.56.Found: C, 58.34, H; 4.94; N, 4.47.

EXAMPLE 3433-((1-(3-(2-(7-Chloro-2-quinolinyl)ethyl)phenyl)-3-(2-cyanophenyl)propyl)thio)-2-ethylpropanoicacid, sodium salt

Using the procedure of Example 40, Steps 1-2, but substitutingN,N-dimethyl 3-mercaptopropanamide by Thiol 13 and starting from2-(3-(3-(2-(7-chloro-2-quinolinyl)ethyl)phenyl)-2-propenyl)benzaldehyde(a precursor of Styrene 2), the title compound was obtained.

¹ H NMR (CD₃ COCD₃) δ: 0.87 (3H, 2t, mixture of diastereomers), 1.61(2H, m), 2.19 (2H, m), 2.30-2.52 (2H, m), 2.52-2.93 (3H, m), 3.20 (2H,t), 3.33 (2H, t), 3.95 (1H, 2t), 7.12-7.45 (7H, m), 7.49 (1H, d), 7.58(1H, dd), 7.69 (1H, d), 7.87 (1H, d), 8.06 (1H, br s), 8.21 (1H, d).

EXAMPLE 3563((3-(4-Chloro-2-(methylaminocarbonyl)phenyl)-1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)propyl)thio)propanoicacid

Using the procedure of Example 229, Step 9, but substituting the thiolof Step 5 by methyl 3-mercaptopropanoate, the thioether was obtainedfrom the lactone of Example 377, Step 3. The methyl amide was thenobtained as in Example 35, Step 2, and the ester was hydrolyzed as inExample 42, Step 2 to yield the title compound.

¹ H NMR (CD₃ COCD₃ -CD₃ SOCD₃) δ: 2:00-2.80 (11H, m), 3.80 (1H, t), 5.40(2H, s), 6.90 (2H, d), 7.05-7.30 (4H, m), 7.55 (1H, dd), 7.70 (1H, d),8.00 (2H, m), 8.10 (1H, m), 8.40 (1H, d).

EXAMPLE 3625-Chloro-2-(3-((2-carboxyethyl)thio)-3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)propyl)benzoicacid Step 1 Methyl5-chloro-2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-hydroxypropyl) benzoate

Sodium methoxide (243 mg, 4.5 mmol) was added to a cold (-5° C.)suspension of the lactone of Example 377, Step 3, (1.4 g, 3 mmol) inMeOH (7 mL) and THF (7 mL). After 15 min. the reaction mixture waswarmed to r.t. and a solution was obtained. After 1 h the mixture waspoured onto aq. saturated NH₄ Cl and the product was extracted withEtOAc, dried over Na₂ SO₄, and the solvents were removed in vacuo toyield 1.48 g (100%) of the title compound.

¹ H NMR (CD₃ COCD₃) δ: 1.95 (2H, m), 2.90 (2H, m), 3.80 (3H, s), 4.4(1H, OH), 5.70 (1H, t), 5.40 (2H, s), 6.95-8.05 (11H, m), 8.30 (1H, d).

Step 2

Using the procedure of Example 366, Steps 11-12 and Example 14, Step 2,the ester of Step 1 was converted to the title diacid.

¹ H NMR (CD₃ COCD₃) δ: 2.0-2.2 (2H, m), 2.4-2.6 (4H, m), 2.70-3.1 (2H,m), 3.9-4.0 (1H, t), 5.4 (2H, s), 6.9-8.05 (11H, m), 8.4 (1H, d).

EXAMPLE 3643-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(2-(1-(hydroxyimino)ethyl)phenyl)propyl)thio)-2-methylpropanoicacid, sodium salt Step 13-(2-Acetylphenyl)-1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)propanol

Using the procedure described in J. Org. Chem., 48, 1550, (1983), MeLiwas added to2-(3-hydroxy-3-(3-(tert-butyldiphenylsiloxy)phenyl)propyl)benzoic acid(Example 229, Step 6) at 0° C. in THF and the mixture was stirred at 0°C. for ≈2 hrs and was quenched with chlorotrimethylsilane to afford themethyl ketone. The silyl ether was then hydrolyzed and the2-quinolinylmethyl ether formed as in Example 229, Step 7-8, to yieldthe title compound.

Step 2

Using the procedure of Example 229, Step 9, the benzylic alcohol of Step1 was reacted with Thiol 4. The ester was then hydrolyzed (Example 42,Step 2) and the oxime was formed by treatment with hydroxylaminehydrochloride (3 equiv) in pyridine at 60° C. for 2 hrs. Formation ofthe sodium salt yielded the title material.

Anal. calcd for C₃₁ H₃₀ ClN₂ O₄ SNa·0.2H₂ O: C, 63.25; H, 5.21; N, 4.76.Found: C, 63.25; H, 5.20; N, 4.69.

EXAMPLE 365(+)-3-((1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-(4-chloro-2-dimethylaminocarbonyl)phenyl)propyl)thio)propanoicacid, sodium salt

The ester from Example 366, Step 7 was converted to the correspondingamide by the methodology of Example 366, Step 10. The secondary alcoholin the amide was then inverted by a Mitsunobu reaction (see Synthesis,1-28 (1981)) and hydrolysis. Using the procedures of Example 366, Steps8, 9, 11, 12 and 13 on the inverted alcohol, the title compound wasobtained as the free acid; [α]_(D) =+74.9° (EtOH, c=3.30).

The title compound was prepared following the procedure of Example 366,Step 14.

EXAMPLE 366(-)3-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(4-chloro-2-(dimethylaminocarbonyl)phenyl)propyl)thio)-propanoicacid, sodium salt Step 1 1-acetoxy-7-chloro-3,4-dihydronaphthalene

To a solution of 7-chlorotetralone (Canadian Patent 974997, Sep. 23,1975) (100 g) in isopropenyl acetate (400 mL) was added conc. H₂ SO₄ (1mL) and the mixture was refluxed for 16 hours then cooled to roomtemperature (r.t.) and evaporated to dryness under reduced pressure. Theresidue was passed through a plug made of celite (100 g) and NaHCO₃ (100g) using ethyl acetate; the filtrate was concentrated in vacuo andpassed through a plug of SiO₂ (12 cm×12 cm) using 30% EtOAc in hexanes,and the fractions containing the product combined and evaporated todryness to yield the title compound as an oil (114 g, 93%), homogeneousby ¹ H NMR.

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.30 (s, 3H, CH₃), 2.35-2.45 (m, 2H, CH₂),2.75-2.85 (m, 2H, CH₂), 5.80 (t, 1H, CH), 7.1 (brs*, 1H, Ar), 7.2 (brs,2H, Ar)

Step 2 2-(3-Oxopropyl)-5-chlorobenzoic acid

To a cold solution (-78° C.) of the crude enol acetate from Step 1 (57g) in CH₂ Cl₂ (250 mL) was added MeOH (50 mL) and the solution treatedwith an ozone/oxygen mixture from a Welsbach T-23 ozonator at -78° untila light blue color persisted. Excess ozone was then blown away with N₂and a CH₂ Cl₂ (200 mL) solution of PPh₃ (80 g) was added at -78° andkept at -78° for 2 hrs; the mixture was then allowed to warm to r.t. andthe solvents were removed on a rotavap. The residue was divided in twoand each portion dissolved in THF (500 mL)-MeOH (150 mL) and thentreated at 0° C. with 1N HCl (150 mL) for 4 hrs. An acid/base work-upusing 10% NaHCO₃ and Et₂ O yielded, after acidification (6N HCl) at 0°C. and extraction into EtOAc, the title compound as a semi-solid residue(39.3 g, 67% combined yield).

¹ H NMR (CD₃ COCD₃) δ (ppm): 2.80-2.90 (t, 2H, CH₂), 3.25-3.35 (t, 2H,CH₂), 7.45-7.65 (m, 2H, Ar), 7.95 (d, 1H, Ar), 9.80 (s, 1H, CHO).

Step 3 3-(t-Butyldiphenylsiloxy)bromobenzene

To a solution of 3-bromophenol (377 g) in CH₂ Cl₂ (2.6 L) was added Et₃N (424 mL) and t-butyldiphenylsilyl chloride (611 g). The reaction wasstirred at r.t. for 3 days, poured onto 4 L of aqueous NH₄ OAc (25%),extracted with Et₂ O, dried and evaporated. Flash chromatography of theresidue using 5% EtOAc/hexane afforded 716 g (80%) of the titlecompound.

¹ H NMR (CDCl₃) δ (ppm): 1.09 (s, 9H), 6.59 (d, 1H), 6.90 (t, 1H) 7.00(m, 2H), 7.33-7.48 (m, 6H), 7.71 (m, 4H).

Step 45-Chloro-2-(3-hydroxy-3-(3-(t-butyldiphenylsiloxy)phenyl)propyl)benzoicacid

To a suspension of Mg (19.9 g, 0.77 mol) in THF (800 ml) was added thebromide from Step 3 (26 g, 64 mmol) and 1,2-dibromoethane (1 mL). Themixture was warmed to initiate the reaction. The remaining bromide (239g, 0.58 mol) in THF (250 mL) was added dropwise over 1 hr. The reactionwas stirred overnight at room temperature. The Grignard solution wasdecanted, using a canula, from the remaining magnesium and used as such.

To the Grignard solution at 0°-5° was added dropwise the aldehyde fromStep 2 (45 g, 0.26 mol) in THF (250 mL). After 1 hour the reaction waspoured into NH₄ Cl (250 g in 2 L H₂ O) and extracted with EtOAc, dried(Na₂ SO₄) and evaporated. Flash chromatography of the residue, using 20%EtOAc in hexane to 40% EtOAc-5% HOAc in hexane, afforded 120 g (92%) ofthe title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 1.05 (s, 9H), 1.80 (q, 2H), 2.95 (m, 2H)4.95 (t, 1H), 6.60 (dd, 1H), 6.90 (m, 2H), 7.05 (t, 1H), 7.20-7.40 (m,1H), 7.35-7.50 (m, 7H), 7.70-7.80 (m, 4H), 7.90 (d, 1H)

Step 5 Methyl5-chloro-2-(3-hydroxy-3-(3-(t-butyldiphenylsiloxy)phenyl)propyl)benzoate

To a suspension of the hydroxy acid (Step 4) (95 g) in acetone (1 L) andK₂ CO₃ (55 g, 2 eq) was added CH₃ I (129 mL 2 eq.) and the mixtureheated to reflux for 16 hr. The reaction mixture was cooled, EtOAc (1 L)was added, and the reaction filtered. Evaporation of the solventsafforded the title compound (93 g).

¹ H NMR (CD₃ COCD₃) δ (ppm): 1.10 (s, 9H), 1.80 (m, 2H), 2.80-3.00 (m,2H), 3.80 (s, 3H), 4.20 (d, 1H), 4.50 (m, 1H), 6.65 (d, 1H), 6.80 (m,2H), 7.05 (t, 1H), 7.23 (m, 1H), 7.30-7.50 (m, 7H), 7.70-7.90 (m, 5H).

Step 6 Methyl5-chloro-2-(3-oxo-3-(3-t-butyldiphenylsiloxy)phenyl)propyl)benzoate

A solution of the alcohol from Step 5 (93 g, 0.18 mol) in CH₂ Cl₂ (0.3L) was added dropwise to a suspension of pyridinium chlorochromate (PCC)(69 g, 0.3 mol) and 4 Å powdered molecular sieves (94 g) in CH₂ Cl₂ (1L) at approx. 10° C. The reaction mixture was stirred for 2 hrs. Ether(1 L) was then added and the mixture was passed through a 500 g pad ofSiO₂. The pad was washed with Et₂ O (2 L) and EtOAc:hexane 1:1 (2 L).The combined filtrates were combined and evaporated. Flashchromatography of the residue using 10% EtOAc in hexane afforded 81 g(87%) of the title compound.

¹ H NMR (CD₃ COCD₃) δ (ppm): 1.15 (s, 9H), 3.10-3.30 (m, 4H) 3.90 (s,3H), 6.90 (s, 1H), 7.30 (t, 1H), 7.40-7.50 (m, 9H), 7.55 (s, 1H),7.70-7.85 (m, 4H), 7.95 (s, 1H).

Step 7 (+) Methyl5-chloro-2-(3-hydroxy-3-(3-(t-butyldiphenylsiloxy)phenyl)propyl)benzoate

To a solution of 44 g (82 mmol) of ketone from Step 6 in 180 mL of THFwas added 1 g of(S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2c]-[1,3,2]oxazaborole(J. Am. Chem. Soc. 109, 7925-6 (1987) at r.t. The solution was cooled to-20°, and 60 ml of borane-THF (1M) solution was added dropwise. Theaddition was completed in ca. 20 min., and the solution was stirred at-20° for 10 min. after addition. The reaction was then quenched by slowaddition of 120 ml of 1N HCl and then partitioned between EtOAc and aq.NaCl. Drying, evaporation and chromatography of the residue on SiO₂ withhexane:EtOAc 4:1 afforded 39 g of the title compound (89%). [α]_(D)=+9.4° (THF, c=4.4).

¹ H NMR (CDCl₃) δ (ppm): 1.10 (s, 9H), 1.87 (m, 2H, CH₂), 2.60 (d, 1H,OH), 2.91 (t, 2H, CH₂), 3.86 (s, 3H, CH₃), 4.53 (t, 1H, CH) 6.63 (d, 1H,arom), 6.78 (s, 1H, arom), 6.88 (d, 1H, arom), 7.00-7.12 (m, 2H, arom),7.38 (m, 7H, arom), 7.72 (d, 4H, arom), 7.90 (d, 1H, arom).

Step 8 Resolved Methyl5-chloro-2-(3-hydroxy-3-(3-hydroxyphenyl)propyl)benzoate

To a solution of 39 g (71 mmol) of the ester from Step 7, and 8 mL ofHOAc in 600 mL of acetonitrile was added slowly 100 mL oftetrabutylammonium fluoride in THF (1M) at r.t. The reaction was stirredfor 2 hr at r.t. and then partitioned between EtOAc and brine.Chromatographic purification on Si₂ O with CH₂ Cl₂ :EtOAc 2:1 gave 22 gof crystalline title compound (93%). Recrystallization fromhexane:EtOAc=2:1 gave 15.7 g of needle-like colorless crystals. From themother liquor 5.5 g more of product were recovered by concentration ofthe solvent.

¹ H NMR (CDCl₃) δ (ppm): 2.02 (m, 2H, CH₂), 3.00 (s, 1H, OH), 3.02 (t,2H, CH₂), 3.88 (s, 3H, CH₃), 4.65 (t, 1H, CH), 5.51 (s, 1H, OH), 6.74(dd, 1H, arom), 6.78 (m, 2H, arom), 7.20 (m, 2H, arom), 7.40 (dd, 1H,arom), 7.38 (d, 1H, arom).

Step 9 (+)-Methyl5-chloro-2-(3-hydroxy-3-(3((7-chloro-2-quinolinyl)methoxy)phenyl)propyl)benzoate

To a solution of 14.5 g (45 mmol) of phenol from Step 8 and 14 g (54mmol) of 2-(bromomethyl)-7-chloroquinoline in 600 ml of acetonitrile wasadded 30 g of K₂ CO₃ at r.t. The mixture was then heated at 70° for 3hr. After cooling, the solid was filtered, the acetonitrile waspartially evaporated and the reaction was partitioned between EtOAc andaq. NH₄ Cl. Drying, evaporation and crystallization from tolueneafforded 14.2 g of the title compound. The mother liquid was purified onSiO₂ with toluene:EtOAc 4:1 to give another 7.5 g of the title compound.Yield: 21.7 g (97%). [α]_(D) =+3.47° (THF, c=1.76).

¹ H NMR (CDCl₃) δ (ppm): 2.00 (m, 2H, CH₂), 2.74 (d, 1H, OH), 2.98 (t,2H, CH₂), 3.89 (s, 3H, CH₂), 4.68 (m, 1H, CH), 5.38 (s, 2H, CH₂), 6.90(dd, 1H), 6.96 (d, 1H), 7.05 (s, 1H), 7.15 (d, 1H), 7.26 (t, 1H), 7.38(dd, 1H), 7.48 (dd, 1H), 7.68 (d, 1H), 7.75 (d, 1H), 7.87 (d, 1H), 8.06(s, 1H), 8.15 (d, 1H).

Step 10(+)N,N-Dimethyl-5-chloro-2-(3-hydroxy-3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-propyl)benzamide

In 100 mL of toluene and 30 mL of 1,2-dichloroethane was dissolved 14 g(28.2 mmol) of ester from Step 9 by warming. To this solution was added110 mL of Me₂ NAlMe₂ in toluene (ca. 0.4M) at 30°. The reaction wasstirred at 70° for 2 hr. and poured into ice cold aq. NH₄ Cl. Theproduct was extracted with EtOAc. After chromatographic purification onsilica gel with toluene:EtOAc 1:1, 13.9 g (96%) of the title compoundwas isolated. [α]_(D) =+15.4° (THF, c=0.91).

¹ H NMR (CDCl₃) δ (ppm): 2.10 (m, 2H, CH₂), 2.71 (t, 2H, CH₂), 2.89 (s,3H, CH₃), 3.15 (s, 3H, CH₃), 4.53 (bt, 1H, CH), 5.38 (s, 2H, CH₂), 6.90(dd, 1H), 6.95 (d, 1H), 7.05 (s, 1H), 7.18-7.38 (m, 4H), 7.53 (dd, 1H),7.71 (d, 1H), 7.78 (d, 1h), 8.09 (s, 1H), 8.18 (d, 1H).

Step 11 ResolvedN,N-dimethyl-5-chloro-2-(3-methane-sulfonyloxy-3-(3-((7-chloro-2-quinolinyl)-methoxy)phenyl)propyl)benzamide

To a solution of 10 g (20 mmol) of amide from Step 10 and 8 ml (56 mmol)of triethylamine in 260 ml of CH₂ Cl₂ was added dropwise 2.2 ml (28mmol) of methanesulfonyl chloride at -40°. The reaction was stirred atthis temperature for 15 min., warmed up to -10° within 30 min. andstirred at -10° for 1 hr. The reaction was quenched by pouring intoice-aq. NaHCO₃ and extracted twice with CH₂ Cl₂. After removal of thesolvent the crude title compound was used as such for the next step.

Step 12 (+)Methyl-3-((1-(3((7-chloro-2-quinolinyl)-methoxy)phenyl)-3-(4-chloro-2-(dimethyl-aminocarbonyl)phenyl)propyl)thio)propanoate

The crude mesylate (ca. 20 mmol) from Step 11 was dissolved in 200 ml ofacetonitrile. To the solution, which was degassed by bubbling argonthrough for a few min., was added 7.2 ml (60 mmol) of methyl3-mercaptopropanoate, followed by 13.7 g (42 mmol) of Cs₂ CO₃. Themixture was stirred at r.t. for 1 hr. The solid was filtered, thereaction was diluted with CH₂ Cl₂ and washed twice with sat. NH₄ Clsolution. Chromatographic purification with toluene:EtOAc 4:1 afforded11 g (90%) of the title compound. [α]_(D) =73° (THF, c=3.5).

¹ H NMR (CDCl₃) δ (ppm): 2.06 (b, 2H, CH₂), 2.36-2.57 (m, 6H, 3CH₂),2.74 (s, 3H, CH₃), 3.00 (s, 3H, CH₃), 3.66 (s, 3H, CH₃), 3.75 (t, 1H,CH), 5.38 (s, 2H, CH₂), 6.92 (d, 1H), 7.01 (s, 1H), 7.03-7.30 (m, 5H),7.51 (dd, 1H), 7.71 (d, 1H), 7.77 (d, 1H), 8.07 (s, 1H), 8.18 (d, 1H).

Step 13

To a solution of 15.9 g of ester from Step 12 in 300 mL of methanol, 80mL of aq. K₂ CO₃ solution (1M) was added. The mixture was stirred undernitrogen at r.t. for 15 hr. The methanol was partially evaporated, andthe reaction was neutralized by addition of 5 ml of HOAc. The productwas then partitioned between aq. NH₄ Cl and EtOAc containing 2% HOAc.The crude product was purified on silica gel with toluene:isopropanol10:1 and then with toluene:isopropanol:acetic acid 10:1:0.1 to give 14.8g (94%) of the title acid. [α]_(D) =-75.1° (THF, c=4.41)

¹ H NMR (CDCl₃) δ: (ppm): 2.07 (b, 2H, CH₂), 2.42-2.60 (m, 6H, 3CH₂),2.75 (s, 3H, CH₃), 3.03 (s, 3H, CH₃), 3.77 (t, 1H, CH), 5.39 (s, 2H,CH₂), 6.90 (d, 1H), 7.03 (s, 1H), 7.06-7.27 (m, 5H), 7.50 (dd, 1H), 7.70(d, 1H), 7.77 (d, 1H), 8.09 (s, 1H), 8.18 (d, 1H).

Step 14

To a solution of the free acid in ethanol, 1 eq. of NaOH was added. Themixture was evaporated and the residue was dissolved in H₂ O and freezedried to yield the title compound.

EXAMPLE 3673-((3-(4-Chloro-2-((ethoxycarbonyl)amino)phenyl)-1-(3-((7-chloro-2-quinolinylmethoxy)phenyl)propyl)thio)-propanoicacid, sodium salt

Methyl 3-mercaptopropanoate was added to the lactone of Example 377,Step 3 (as in Example 229, Step 9), to yield a benzylic thioether. Theacid function was then converted to the amine as described in thepreparation of styrene 8, Step 1. Then, the carbamate was obtained byreaction with ethyl chloroformate and N-methylmorpholine in CH₂ Cl₂ atr.t. in the presence of a catalytic amount of 4-(dimethylamino)pyridine.Finally, the ester was hydrolyzed as in Example 42, Step 2, to yield thetitle sodium salt.

Anal. calcd for C₃₁ H₂₉ Cl₂ N₂ O₅ SNa·0.5H₂ O: C, 57.77; H, 4.69; N,4.35. Found: C, 57.93; H, 4.58; N, 4.15.

EXAMPLE 3683-((3-(2-Chloro-6-(dimethylaminocarbonyl)phenyl)-1-(3-((7chloro-2-quinolinyl)methoxy)phenyl)propyl)thio)-propanoicacid

Starting from 5-chloro-1-tetralone (Can. Pat. 048,579) and using theprocedure of Example 366, Steps 1-5 and 8-13, the title compound wasobtained.

¹ H NMR (CD₃ COCD₃) δ: 1.90-3.10 (15H, m), 4.00 (1H, t), 5.35-5.55 (2H,AB), 6.95-8.05 (11H, m), 8.40 (1H, d).

EXAMPLE 3693-((3-(4-Chloro-2-(dimethylaminocarbonyl)phenyl)-1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)propyl)sulfinyl)propanoic acid, sodium salt

To a solution of the title compound of Example 109 (300 mg, 0.502 mmol)in CH₂ Cl₂ (2.5 mL) at 0° C. was added a solution of 85% m-CPBA(meta-chloroperbenzoic acid) (96 mg, 0.555 mmol) in CH₂ Cl₂ (1 mL). Whenthe reaction was completed (as shown by TLC with 40% acetone intoluene), 25% aq NH₄ OAc was added. The product was extracted withEtOAc, dried over Na₂ SO₄, filtered and evaporated at reduced pressure.The resulting mixture was purified by flash chromatography to provide220 mg (73%) of the title acid, which was converted to its sodium salt(Example 366, Step 13).

¹ H NMR (CD₃ SOCD₃) δ: 1.9-2.6 (8H, m), 2.63, 2.65, 2.85 and 2.90 (6H,4s), 3.80 (1H, m), 5.40 (2H, s), 6.90 (1H, m), 7.15 (2H, m), 7.20-7.40(4H, m), 7.65 (1H, dd), 7.75 (1H, d), 8.05 (2H, m), 8.50 (1H, d).

EXAMPLE 3703-((3-(3-Chloro-2-(dimethylaminocarbonyl)phenyl)-1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)thio)propanoicacid, sodium salt Step 1 N,N-Dimethyl2-chloro-6-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-oxo-1-propenyl)benzamide

Using the procedure of Example 366, Step 10, Me₂ AlNMe₂ was added to7-chloro-3-hydroxy-1-(3H)-isobenzofuranone (J. Org. Chem., 49, 1078(1984)) to give N,N-dimethyl 2-chloro-6-formylbenzamide. This aldehydewas then reacted with the ylid of Example 379, Step 3 as in Example 379,Step 5 to afford the title compound.

Step 2 N,N-Dimethyl2-chloro-6-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-oxopropyl)benzamide

To a r.t. solution of the olefin of Step 1 (1.37 g, 2.71 mmol) in MeOH(10 mL) was added tris(triphenylphosphine)rhodium (I) chloride (200 mg)and the reaction was put under an H₂ atmosphere for 16 h. The reactionwas filtered through celite, the solvent removed in vacuo and theresidue passed over a plug of SiO₂ with EtOAc:hexanes 1:1. The wholeoperation was repeated to yield 700 mg of the title compound.

¹ H NMR (C₆ D₆) δ: 2.25 (3H, s), 2.70 (3H, s), 2.80-3.20 (3H, m),3.35-3.75 (1H, m), 5.10 (2H, s), 6.70-7.50 (10H, m), 7.85 (1H, br d),8.30 (1H, br d).

Step 3

Using the procedures of Example 29, Method B, Step 1 and of Example 366,Steps 11-13, the title compound was obtained.

Anal. calcd for C₃₁ H₂₉ Cl₂ N₂ O₄ SNa·1.5H₂ O: C, 57.59; H, 4.99; N,4.33. Found: C, 57.47; H, 5.03; N, 4.40.

EXAMPLE 3723-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(2-(1H-tetrazol-5-yl)phenyl)propyl)thio)-2-methylpropanoicacid, disodium salt Step 1 3-Mercapto-2-methylpropanoic acid

Using the procedure of Example 113, Steps 1-2, ethyl3-mercapto-2-methylpropanoate was obtained from ethyl methacrylate. Theester was then hydrolyzed as in Example 1, Step 8, to give the titlethiol, which was purified by distillation; b.p.≈100° C/0.5 mm Hg.

Step 2

Using the procedure of Example 40, but substituting N,N-dimethyl3-mercapto-propanamide by 3-mercapto-2-methylpropanoic acid in Step 2and using 2 equivalents of NaOH for the formation of the sodium salt inStep 3, the title compound was prepared.

Anal. calcd for C₃₀ H₂₆ ClN₅ O₃ SNa₂ ·6H₂ O: C, 49.62; H, 5.27; N, 9.64.Found: C, 49.48; H, 5.29; N, 9.51.

EXAMPLE 3733-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(2-(aminocarbonyl)phenyl)propyl)thio)-2-methylpropanoicacid, sodium salt

Methyl2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-2-propenyl)benzoate(Example 29, Method B, Step 6) was hydrolyzed to the acid using theprocedure of Example 29, Method A, Step 3. Using the procedure ofExample 35, Step 2, but replacing tert-butylamine by ammonia, the amidewas obtained. Then, 3-mercapto-2-methylpropanoic acid (Example 372,Step 1) was added as in Example 29, Method A, Step 1. The title sodiumsalt was finally obtained with one equivalent of NaOH as in Example 14,Step 2.

Anal. calcd for C₃₀ H₂₈ ClN₂ O₄ SNa·H₂ O: C, 61.17; H, 5.13; N, 4.76;Cl, 6.02. Found: C, 61.27; H, 4.94; N, 4.93; Cl, 6.28.

EXAMPLE 374 (+)3-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(2-(dimethylaminocarbonyl)phenyl)propyl)thio)propanoicacid, sodium salt Step 1 (+) N,N-Dimethyl2-(3-hydroxy-3-(3-tert-butyldiphenylsiloxy)phenyl)propyl)benzamide

Starting from α-tetralone and using the procedure of Example 366, Steps1-6, methyl 2-(3-oxo-3-(3-(tert-butyldiphenylsiloxy)phenyl)propyl)benzoate was prepared. The ketone was reduced as in Example 366, Step 7,to afford the chiral alcohol. Finally, the ester was reacted with Me₂AlNMe₂ as in Example 366, Step 10, to give the title compound. [α]_(D)+16.9 (c=0.75, THF)

¹ H NMR (CDCl₃)δ: 1.1 (9H, s), 1.9 (2H, m), 2.65 (2H, t), 2.8 (3H, s),3.1 (3H, s), 4.35 (1H, m), 6.55 (1H, d), 6.75 (1H, s), 6.8 (1H, d), 7.0(1H, t), 7.2 (4H, m), 7.4 (6H, m), 7.7 (4H, m).

Step 2

The secondary alcohol of Step 1 was inverted using a Mitsunobu reaction(see Synthesis, 1 (1981)) and hydrolysis as in Example 1, Step 8 toafford (-) N,N-dimethyl 2-(3-(3-hydroxyphenyl)-3-hydroxypropyl)benzamide[α]_(D) -34.1 (c=1.10, THF). Finally, using the procedure of Example366, Steps 9, 11-13, the phenol was converted to the title acid. [α]_(D)+72.9 (c=1.5, EtOH).

¹ H NMR (CDCl₃) δ: 2.1 (2H, m), 2.45-2.6 (6H, m), 2.75 (3H, s), 3,1 (3H,s), 3.8 (1H, t), 5.38 (2H, s), 6.91 (2H, m), 7.05 (1H, s), 7.1-7.3 (5H,m), 7.5 (1H, dd), 7.7 (1H, d), 7.8 (1H, d), 8.1 (1H, s), 8.2 (1H, d).

For the title sodium salt:

Anal. calcd for C₃₁ H₃₀ ClN₂ O₄ SNa·0.3H₂ O: C, 63.06; H, 5.22; N, 4.74.Found: C, 63.03; H, 5.15; N, 4.66.

EXAMPLE 375 (-)3-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(2-(dimethylaminocarbonyl)phenyl)propyl)thio)propanoicacid, sodium salt

Using the procedure of Example 374, but omitting the inversion of thechiral benzylic alcohol, the title compound was obtained. [α]_(D) of theacid -68° (c=1.10, EtOH).

Anal. calcd for C₃₁ H₃₀ ClN₂ O₄ SNa·H₂ O: C, 62.78; H, 5.27; N, 4.72.Found: C, 62.55; H, 5.25; N, 4.62.

EXAMPLE 3765-Bromo-2-(3-((2-carboxyethyl)thio)-3-(3-((7-chloro-2-quinolinyl)methoxy)phenylpropyl)benzoicacid. disodium salt

Using the procedures of Example 366, Steps 1-5, 8, 9, 11, 12 and Example14, Step 2, 7-bromo-1-tetralone was converted to the title compound.

Anal. calcd for C₂₉ H₂₃ NO₅ SClBrNa₂ ·1H₂ O: C, 51.46; H, 3.72; N, 2.07,Br, 11.8. Found: C, 51.02; H, 3.47; N, 1.98; Br, 11.35.

EXAMPLE 3773-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(4-chloro-2-(dimethylaminocarbonyl)phenyl)propyl)thio)butanoicacid, sodium salt Step 1 Methyl 3-(acetylthio)butanoate

A mixture of thiolacetic acid (15.2 g, 199 mmol) and methyl crotonate(10.0 g, 100 mmol) was heated at 70° C. After 2 days, the reactionmixture was allowed to cool to r.t. 25% aq NH₄ OAc was added and theproduct was extracted with EtOAc, dried over Na₂ SO₄ and evaporatedunder reduced pressure. The title compound was distilled (75° C./0.5 mmHg) as a yellow oil (14.8 g, 90.0%).

¹ H NMR (CD₃ COCD₃) δ: 1.35 (3H, d), 2.26 (3H, s), 2.63 (2H, m), 3.65(3H, s), 3.85 (1H, m).

Step 2 Methyl 3-mercaptobutanoate

To a solution of the ester of Step 1 (5.0 g, 28.4) in MeOH (140 mL) at0° C. was added K₂ CO₃ (32.0 g, 231 mmol). After 15 min, the reactionwas quenched by the addition of 25% aq. NH₄ OAc and the title compoundwas extracted with EtOAc, dried with Na₂ SO₄ and evaporated. The titlethiol was obtained at a colorless oil (3.00 g, 79%).

¹ H NMR (CD₃ COCD₃) δ: 1.30 (3H, d), 2.13 (1H, d), 2.55 (2H, m), 3.30(1H, m), 3.62 (3H, s).

Step 38-Chloro-3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-4,5-dihydro-2-benzoxepin-1(3H)-one

Using the procedure of Example 229, Steps 6-8, the hydroxyacid ofExample 366, Step 4, was converted to the title lactone.

¹ H NMR (CD₃ COCD₃) δ: 2.35 (2H, m), 3.00 (2H, m), 5.15 (1H, dd), 5.47(2H, s), 7.00 (2H, m), 7.23 (1H, d), 7.29 (1H, t), 7.40 (1H, d), 7.60(3H, m), 7.75 (1H, d), 8.00 (2H, m), 8.40 (1H, d).

Step 4

Using the procedure of Example 229, Step 9, the thiol of Step 2 wasadded to the lactone of Step 3. Then using the procedure of Example 229,Step 10, but replacing ammonia for dimethylamine, the title compound wasobtained.

Anal. calcd for C₃₂ H₃₁ Cl₂ N₂ O₄ SNa·H₂ O: C, 59.03; H, 5.06; N, 4.30.Found: C, 59.38; H, 5.05; N, 4.33.

EXAMPLE 3793-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(5-(dimethylaminocarbonyl)-2-furanyl)propyl)thio)propanoicacid, sodium salt Step 11-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)ethanone

To 3-((7-chloro-2-quinolinyl)methoxy)benzaldehyde, MeMgBr was added (inTHF at 0° C.) to give an ethanol derivative, which was oxidized to thetitle compound as in Example 29, Method B, Step 5.

¹ H NMR (CD₃ COCD₃) δ: 2.56 (s, 3H, CH₃ CO), 5.44 (s, 2H, OCH₂) 7.34 (m,1H), 7.44 (m, 1H), 7.5-7.7 (m, 3H), 7.72 (d, 1H, J=8.6 Hz), 7.95-8.10(m, 2H), 8.41 (d, 1H, J=8.6 Hz)

Step 2 2-Bromo-1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)ethanone

A solution of the ketone of Step 1 (10.9 g, 35 mmol) in HOAc (210 mL)was treated with NaBrO₃ (1.75 g, 11.7 mmol) in H₂ O (35 mL), and then48% HBr (35 mL) was added dropwise. The yellow suspension was stirredfor 5 min. and then the flask was transferred to an oil-bath preheatedto 105° C. In 11 min, the solid had dissolved. After stirring at 105° C.for a further 5 min, the reaction mixture was cooled in an ice-bathbefore collecting the hydrobromide of the product.

The free base was isolated by basification with NaHCO₃ and extractionwith EtOAc. The solid was slurried with diisopropyl ether, filtered offand dried to give 9.08 g (66%) of the title compound, m.p. 110°-112° C.

Step 31-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-2-(triphenylphosphoranylidine)ethanone

A solution of the bromoketone of Step 2 (8.78 g, 22.5 mmol) andtriphenylphosphine (5.90 g, 22.5 mmol) in CH₂ Cl₂ (45 mL) was allowed tostand at room temperature for 2 h. 1N NaOH (66 mL) was added, and themixture was stirred vigorously for 2 hours. Addition of toluene andevaporation of the CH₂ Cl₂ gave 11.44 g (89%) of the title product as asolid, m.p. 187°-188° C.

Anal. calcd for C₃₆ H₂₇ ClNO₂ P: C, 75.59; H, 4.76; N, 2.45; P, 5.41.Found: C, 75.42; H, 4.75; N, 2.61; P, 5.03.

Step 4 N,N-Dimethyl-5-formyl-2-furan-carboxamide

N,N-Dimethyl-2-(2-Furanyl)imidazoline (A. J. Carpenters and D. J.Christwick, Tetrahedron, 41, 3803 (1985)) (8.25 g, 50 mmol) in dry THF(125 mL) was lithiated with 1.6M n-butyl lithium (33 mL). After 2 h at-78° C., the solution was transferred by a cannula to a stirred solutionof dimethylcarbamoyl chloride (5.0 mL, 54.5 mmol) in THF (10 mL) at-100° C. Stirring at -100° C. was continued for 15 min, and then themixture was allowed to attain room temperature. After another 2 h, 1M H₂SO₄ (150 mL) was added and the mixture was stirred for an hour.Extraction with EtOAc (5×100 mL) gave a crude product which was purifiedby column chromatography (200 g of silica gel eluted with 1:2EtOAc:hexane containing 10% of tert-butanol) to give 5.45 (65%) of titleproduct, m.p. 75°- 76° C.

Anal. calcd for C₈ H₉ NO₃ : C, 57.48; H, 5.43; N, 8.38. Found: C, 57.57;H, 5.18; N, 8.07.

Step 5 N,N-Dimethyl5-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-oxo-1-propenyl)-2-furancarboxamide

A mixture of the furancarboxaldehyde of Step 4 (1.25 g, 7.5 mmol), thephosphoranylidene of Step 3 (4.29 g, 7.5 mmol) and toluene (43 mL) washeated at 80° C. for 4 h. When cool, a small amount of insolublematerial was filtered off, and the solution was evaporated onto silicagel (30 g). The solid was placed on top of a column of silica gel (300g), and eluted with 1:10:100:100 formic acid:tert-butanol:ethylacetate:toluene to yield 4.78 g of a mixture. Recrystallization of thissolid from acetonitrile (25 mL) gave the title product 2.52 g (73%),m.p. 141°-142° C.

Anal. calcd for C₂₆ H₂₁ ClN₂ O₄ : C, 67.75; H, 4.59; Cl, 7.69; N, 6.08.Found: C, 67.49; H, 4.49; Cl, 7.88; N, 6.13.

Step 6 N,N-Dimethyl5-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-oxopropyl)-2-furancarboxamide

Tellurium (650 mg, 5 mmol) was dissolved in EtOH (20 mL) containingNaBH₄ (450 mg, 11.8 mmol). Reaction started spontaneously, and wascompleted by heating at reflux for 30 min. The unsaturated ketone ofStep 5 (920 mg, 2 mmol) was added, and the mixture was stirred at roomtemperature for 7 hours. Methanol (20 mL) was added, and the solutionwas filtered through celite. After evaporation, the product was isolatedby partitioning between a mixture of Et₂ O, EtOAc and H₂ O, followed bycolumn chromatography (silica gel eluted with 1:2 EtOAc:hexanecontaining 10% of tert-butanol) to yield 246 g (27%), mp 129°-131° C.

Step 7

Using the procedures of Example 29, Method B, Steps 1 and 2, the ketoneof Step 6 was converted to the benzylic bromide, which was reacted withmethyl 3-mercaptopropanoate in the presence of Cs₂ CO₃ in acetonitrile.Finally, hydrolysis of the ester as in Example 29, Method A, Step 3 with2 equiv of NaOH afforded the title product.

Anal. calcd for C₂₉ H₂₈ ClN₂ O₅ Na·2H₂ O: C, 57.00; H, 5.28;, N, 4.54.Found: C, 57.37; H, 4.93; N, 4.28.

EXAMPLE 3813-((3-(2-(Acetylamino)-4-chlorophenyl)-1-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)propyl)thio)propanoicacid

To the aniline prepared as an intermediate in Example 367 (440 mg, 0.8mmol), dissolved in CH₂ Cl₂ at room temperature were added triethylamine(660 μL, 4.8 mmol), acetyl chloride (170 μL, 2.4 mmol) and4-dimethylaminopyridine (10 mg, 0.08 mmol). The solution was stirred 5hours before adding a saturated aqueous solution of NH₄ Cl. Extractionwith CH₂ Cl₂ followed by drying over MgSO₄ and evaporation of thesolvent in vacuo gave the crude product as a solid. The pure amide (267mg) was obtained along with an impure fraction (217 mg) simply byswishing it in Et₂ OAc 95:5 followed by filtration and drying. The esterwas then hydrolyzed as in Example 42, Step 2 to give the title acid.

¹ H NMR (CD₃ COCD₃) δ: 2.02 (3H, s), 2.10 (2H, m), 2.35-2.80 (6H, m),3.88 (1H, dd), 5.40 (2H, s), 6.95-7.35 (6H, m), 7.60 (1H, dd), 7.75 (2H,br d), 8.0 (1H, d), 8.05 (1H, d), 8.40 (1H, d), 8.55 (1H, br s, NH).

EXAMPLE 3823-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(4-chloro-2-(((methylsulfonyl)amino)carbonyl)phenyl)propyl)thio)propanoicacid, disodium salt

Methyl 3-mercaptopropanoate was added to the lactone of Example 377,Step 3 (as in Example 229, Step 9) to yield a benzylic thioether. Usingthe procedure of Example 152, Steps 2-3, but substitutingp-toluenesulfonamide in Step 2 for methylsulfonamide, the title compoundwas obtained.

Anal. calcd for C₃₀ H₂₆ Cl₂ N₂ O₆ S₂ Na₂ : C, 52.10; H, 3.79; N, 4.05.Found: C, 52.20; H, 3.69; N, 4.77.

EXAMPLES 383, 384 AND 388

Using the procedure of Example 229, Step 9 and Example 42, Step 2, thelactone of Example 377, Step 3, was converted to the followingcompounds. For Examples 383 and 384, Thiols 5 and 13 were used in placeof methyl 3-mercapto-2-methoxypropanoate.

EXAMPLE 3835-Chloro-2-(3-((2-carboxybutyl)thio)-3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)propyl)benzoicacid, disodium salt.

Anal. calcd for C₃₁ H₂₇ Cl₂ NO₅ SNa₂ ·0.5H₂ O: C, 57.15; H, 4.33; N,2.15. Found: C, 57.00; H, 4.32; N, 2.11.

EXAMPLE 3845-Chloro-2-(3-((2-carboxypropyl)thio)-3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)propyl)benzoicacid, disodium salt.

Anal. calcd for C₃₀ H₂₅ Cl₂ NO₅ SNa₂ ·0.5H₂ O: C, 56.52; H, 4.11; N,2.20. Found: C, 56.73; H, 4.13; N, 2.18.

EXAMPLE 3885-Chloro-2-(3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)-3-(2-carboxy-2-methoxyethyl)thio)propyl)benzoicacid, disodium salt.

Anal. calcd for C₃₀ H₂₅ Cl₂ NO₆ SNa₂ ·0.5H₂ O: C, 55.14; H, 4.01; N,2.14. Found: C, 54.71; H, 3.72; N, 2.05.

EXAMPLE 3952-(3-((2-Carboxyethyl)thio)-3-(3-((7-chloro-2-quinolinyl)methoxy)phenyl)propyl)-5-phenylbenzoicacid

The diacid of Example 376 (380 mg, 0.6 mmol) and phenylboronic acid (295mg, 2.4 mmol) were placed in a 2 neck flask which was purged 5 minuteswith nitrogen. Toluene (6 mL) and 2M aqueous Na₂ CO₃ (1.2 mL) wereintroduced and the flask was purged again by 3 cycles of vacuum andnitrogen flushing. Tetrakis(triphenylphosphine)palladium (0) (45 mg,0.06 mmol) was added and the resulting mixture was refluxed for 4 hourswith careful exclusion of air. The mixture was then cooled to roomtemperature, 1M HCl was added and the aqueous phase was extracted withEtOAc. The combined organic phases were dried over MgSO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyon SiO₂ (17:80:3 EtOAc:toluene:acetone) to give the title compound (340mg).

¹ H NMR of the diacid (CD₃ COCD₃) δ: 2.18 (2H, m), 2.43 (2H, m), 2.55(2H, m), 2.88 (1H, m), 3.05 (1H, m), 3.98 (1H, dd), 5.42 (2H, s), 7.0(2H, m), 7.15-7.8 (11H, m), 7.98 (1H, d), 8.05 (1H, d), 8.18 (1H, d),8.40 (1H, d).

EXAMPLE 4003-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(2-(dimethylaminocarbonyl)-3-pyridinyl)propyl)thio)propanoicacid, sodium salt

Ketoester 2 was reacted with 2-propyl3-(bromomethyl)-2-pyridinecarboxylate (J. Med. Chem., 1989, 32, 827) asin Example 402, Step 3, except that the treatment with MeI/K₂ CO₃ wasavoided, to give a ketoester. The ketone was reduced with NaBH₄ (Example402, Step 4), the ester was hydrolyzed with NaOH, and the hydroxyacidwas lactonized (Example 229, Step 6). The title product was obtainedfrom the lactone as in Example 366, Steps 10-13.

Anal. calcd for C₃₀ H₂₉ ClN₃ O₄ SNa: C, 61.48; H, 4.99; N, 7.17. Found:C, 61.62; H, 5.18; N, 7.06.

EXAMPLE 4023-((3-(4-Chloro-2-(dimethylaminocarbonyl)phenyl)-1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)propyl)thio)propanoicacid Step 1 1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)ethanone

To 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde, MeMgBr was added(in THF at 0° C.) to give an ethanol derivative, which was oxidized tothe title compound as in Example 29, Method B, Step 5.

¹ H NMR (CD₃ COCD₃) δ: 2.68 (3H, s), 7.55-7.68 (3H, m), 7.89-8.05 (6H,m), 8.36 (2H, m).

Step 2 Methyl3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-oxopropanoate

In a 500 mL flask fitted with a condenser were suspended the ketone ofStep 1 (57.05 g, 185 mmol) and dimethylcarbonate (13.70 mL, 2.5 equiv.)in THF (230 mL). 80% NaH (16.70 g, 3 equiv.) was added portionwise overa few minutes and the reaction was initiated through the addition ofMeOH (370/l). The mixture was stirred at r.t. The solids graduallydissolved and when the evolution of hydrogen has subsided, the mixturewas heated at 70° C. for 1 h. After cooling to r.t., it was poured ontocold 25% aq NH₄ OAc. The solid was collected and air dried and swishedin EtOH (600 mL) containing EtOAc (50 mL) for 18 h. The title compoundwas collected as a pale beige solid, 60.3 g, 89%.

¹ H NMR (CD₃ COCD₃) δ: 3.70 (s, 3H); 3.73 (small peak, OCH₃ of enolform); 7.45-7.70 (m, 6H); 7.80-8.10 (m, 3H), 8.36 (d, 2H).

Step 3 Methyl2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-oxopropyl)benzoate

To a solution of the β-ketoester of Step 2 (50.0 g, 0.136 mol) and theiodide 1 (41.5 g, 1.1 equiv.) in DMF at 0° C. was added 80% NaH (4.51 g,1.1 equiv.). The ice bath was removed and the mixture was stirred atr.t. After 2 h, when no starting material remained, the reaction mixturewas poured onto cold 25% aq NH₄ OAc. The solid collected was swished inEtOH (60 mL) overnight to afford 60.0 g (97%) of the pure adduct.

The above material was suspended in EtOAc/conc. HCl mixture (1.2 L/240mL) and heated at 90° C. for 4 h. After it was cooled to r.t., it waspoured onto cold aq NH₄ Cl. The solid was collected and air dried.

The above mixture (containing the title ester and its acid) wassuspended in acetone (500 mL) containing MeI (4.25 mL) and powdered K₂CO₃ (18 g). The mixture was heated at 50° C. for 3 h until themethylation was complete. The reaction mixture was partitioned betweenEtOAc and H₂ O. The aqueous phase was extracted with EtOAc (x2) and thecombined organic phase was washed with brine, dried and concentrated.The resulting residue was recrystallized from EtOAc:hexane 1:1 to afford37.7 g (53%) of the title compound.

Step 4 Methyl2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl)benzoate

To a solution of the ketone of Step 3 (4.24 g, 9.31 mmol) in THF (60 mL)and MeOH (20 mL) at 0° C. was added in one portion NaBH₄ (460 mg, 1.3equiv.). The mixture was stirred for 30 min at r.t. and the reaction wasquenched by the addition of acetone (≈1 mL). The solvent was removed andthe residue was partitioned between EtOAc and H₂ O. Conventional work-upof the organic phase gave a residue which was purified by flashchromatography (EtOAc:hexane 1:3 and 1:2) to give 3.84 g (90%) of thetitle compound as a foam.

Step 5

Using the procedure of Example 366, Steps 10-13, the title compound wasobtained.

¹ H NMR (CD₃ COCD₃) δ: 2.20 (2H, m), 2.45-2.75 (6H, m), 2.78 (3H, s),2.97 (3H, s), 4.03 (1H, t), 7.19 (1H, s), 7.33 (2H, s), 7.39-7.55 (4H,m), 7.65 (1H, m), 7.77 (1H, s), 7.85-8.02 (4H, m), 8.33 (1H, d).

EXAMPLE 4033-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(4-chloro-2-(1H-tetrazol-5-yl)phenyl)propyl)thio)propanoicacid, disodium salt

Using the procedure of Example 366, Step 10, but using Me₂ AlNH₂ at 75°C., the lactone of Example 377, Step 3, was opened to thehydroxynitrile. Then, using the procedures of Examples 366, Steps 11-12,Example 41, Step 4 and Example 366, Step 13, the title tetrazole wasobtained.

¹ H NMR (disodium salt) (CD₃ COCD₃ :CD₃ SOCD₃) δ: 1.95-2.30 (4H, m),2.40-2.60 (2H, t), 2.75-2.90 (1H, m), 3.10-3.30 (1H, m), 3.85-3.95 (1H,t), 5.40 (2H, s), 6.90-7.30 (7H, m), 7.60-8.10 (4H, m), 8.5 (1H, d).

Anal. calcd for C₂₉ H₂₃ Cl₂ N₅ O₃ SNa₂ ·3H₂ O: C, 50.30; H, 4.22; N,10.11. Found: C, 50.54; H, 4.24; N, 10.12.

EXAMPLE 4043-((1-(3-((7-Chloro-2-quinolinyl)methoxy)phenyl)-3-(2-cyanophenyl)propyl)thio)-2-methylpropanoicacid, sodium salt

The acid of the title compound was obtained as the last intermediate inthe synthesis of the product of Example 372 (before the treatment withBu₃ SnN₃). The sodium salt was obtained as in Example 372 except thatone equiv. of NaOH was used.

Anal. calcd for C₃₀ H₂₆ ClN₂ O₃ SNa·0.7H₂ O: C, 63.70; H, 4.88; N, 4.95.Found: C, 63.71; H, 4.83; N, 4.74.

EXAMPLE OF TABLE 2

Using the procedure of Examples 43, 113, 373 and 29, Method B, thecompounds of Table 2 were obtained from Styrenes 1-9 and methyl2-(3-(3((6-methoxy-2-quinolinyl)methoxy)phenyl)-2-propenyl)benzoate(obtained from Quinoline 4 and 3-hydroxybenzaldehyde, using theprocedures of Example 366, Step 9 and Example 29, Method B, Steps 1-6),Thiols 1-12 and the following amines: ammonia, methylamine,dimethylamine, ethylamine, diethylamine, tert-butylamine,iso-butylamine, piperidine, pyrolidine and morpholine.

                                      TABLE 2                                     __________________________________________________________________________                      Calculated                                                                              Found                                             Ex.                                                                              Formula        C  H  N   C  H  N                                           __________________________________________________________________________     54                                                                              C.sub.30 H.sub.28 ClN.sub.2 O.sub.4 SNa.1.5H.sub.2 O                                         60.24                                                                            5.22                                                                             4.68                                                                              60.56                                                                            5.31                                                                             4.53                                         65                                                                              C.sub.32 H.sub.34 N.sub.2 O.sub.4 S                                                          NMR data below                                               68                                                                              C.sub.34 H.sub.34 ClN.sub.2 O.sub.4 SNa.0.5H.sub.2 O                                         64.40                                                                            5.56                                                                             4.42                                                                              64.19                                                                            5.46                                                                             4.35                                         69                                                                              C.sub.33 H.sub.32 ClN.sub.2 O.sub.5 SNa.H.sub.2 O                                            61.42                                                                            5.23                                                                             4.34                                                                              61.22                                                                            5.25                                                                             4.23                                         75                                                                              C.sub.32 H.sub.32 ClN.sub.2 O.sub.4 SNa.1.7H.sub.2 O                                         61.03                                                                            5.67                                                                             4.45                                                                              60.90                                                                            5.41                                                                             4.35                                         91                                                                              C.sub.32 H.sub.32 ClN.sub.2 O.sub.3 SNa.1.5H.sub.2 O                                         62.99                                                                            5.78                                                                             4.59                                                                              62.99                                                                            5.58                                                                             4.48                                         92                                                                              C.sub.33 H.sub.34 ClN.sub.2 O.sub.3 SNa.0.5H.sub.2 O                                         65.39                                                                            5.82                                                                             4.62                                                                              65.96                                                                            6.45                                                                             4.39                                         95                                                                              C.sub.33 H.sub.34 ClN.sub.2 O.sub.4 SNa.0.3H.sub.2 O                                         64.08                                                                            5.64                                                                             4.53                                                                              64.16                                                                            5.68                                                                             3.94                                         97                                                                              C.sub.32 H.sub.30 ClN.sub.2 O.sub.3 SNa                                                      NMR data below                                               99                                                                              C.sub.31 H.sub.29 ClN.sub.2 O.sub.3 S                                                        NMR data below                                              100                                                                              C.sub.33 H.sub.34 ClN.sub.2 O.sub.4 SNa.H.sub.2 O                                            62.75                                                                            5.78                                                                             4.43                                                                              62.90                                                                            5.64                                                                             4.30                                        103                                                                              C.sub.34 H.sub.36 ClN.sub.2 O.sub.3 SNa.0.5H.sub.2 O                                         65.75                                                                            6.15                                                                             4.67                                                                              65.85                                                                            6.01                                                                             4.52                                        104                                                                              C.sub.33 H.sub.34 ClN.sub.2 O.sub.4 SNa.0.5H.sub.2 O                                         63.70                                                                            5.67                                                                             4.5  0.30                                             106                                                                              C.sub.33 H.sub.32 ClN.sub.2 O.sub.4 SNa.0.5H.sub.2 O                                         63.90                                                                            5.32                                                                             4.51                                                                              64.02                                                                            5.42                                                                             4.39                                        107                                                                              C.sub.33 H.sub.32 ClN.sub.2 O.sub.4 SNa.0.5H.sub.2 O                                         63.91                                                                            5.36                                                                             4.52                                                                              63.65                                                                            5.40                                                                             4.40                                        108                                                                              C.sub.34 H.sub.34 ClN.sub.2 O.sub.3 SNa.H.sub.2 O                                            65.11                                                                            5.79                                                                             4.47                                                                              64.77                                                                            5.92                                                                             4.12                                        112                                                                              C.sub.33 H.sub.32 ClN.sub.2 O.sub.3 SNa.0.5H.sub.2 O                                         65.60                                                                            5.51                                                                             4.64                                                                              65.70                                                                            5.59                                                                             4.42                                        114                                                                              C.sub.31 H.sub.30 ClN.sub.2 O.sub.3 SNa.H.sub.2 O                                            63.41                                                                            5.49                                                                             4.77                                                                              63.50                                                                            5.21                                                                             4.68                                        115                                                                              C.sub.32 H.sub.32 ClN.sub.2 O.sub.3 SNa.2H.sub.2 O                                           62.08                                                                            5.86                                                                             4.52                                                                              62.50                                                                            5.79                                                                             4.36                                        116                                                                              C.sub.31 H.sub.28 ClNO.sub.4 SNa.sub.2.1.5H.sub.2 O                                          60.14                                                                            5.05                                                                             2.26                                                                              60.17                                                                            4.89                                                                             2.22                                        118                                                                              C.sub.32 H.sub.32 ClN.sub.2 O.sub.4 SNa.1.5H.sub.2 O                                         61.38                                                                            5.63                                                                             4.47                                                                              61.58                                                                            5.55                                                                             4.27                                        119                                                                              C.sub.33 H.sub.34 ClN.sub.2 O.sub.4 SNa.0.6H.sub.2 O                                         63.51                                                                            5.68                                                                             4.48                                                                              63.40                                                                            5.76                                                                             4.29                                        120                                                                              C.sub.31 H.sub.30 ClN.sub.2 O.sub.4 SNa.1.2H.sub.2 O                                         61.36                                                                            5.34                                                                             4.61                                                                              61.33                                                                            5.33                                                                             4.39                                        121                                                                              C.sub.34 H.sub.36 ClN.sub.2 O.sub.4 SNa.0.6H.sub.2 O                                         64.00                                                                            5.83                                                                             4.34                                                                              64.12                                                                            5.91                                                                             4.23                                        122                                                                              C.sub.32 H.sub.32 ClN.sub.2 O.sub.4 SNa.0.5H.sub.2 O                                         63.20                                                                            5.47                                                                             4.61                                                                              63.08                                                                            5.53                                                                             4.38                                        126                                                                              C.sub.32 H.sub.32 ClN.sub.2 SO.sub.3 Na.1.5H.sub.2 O                                         63.04                                                                            5.65                                                                             4.58                                                                              63.38                                                                            5.66                                                                             4.52                                        154                                                                              C.sub.31 H.sub.30 ClN.sub.2 O.sub.4 SNa.0.7H.sub.2 O                                         62.30                                                                            5.30                                                                             4.69                                                                              62.32                                                                            5.17                                                                             4.63                                        157                                                                              C.sub.32 H.sub.32 ClN.sub.2 O.sub.4 SNa.5H.sub.2 O                                           55.77                                                                            6.14                                                                             4.06                                                                              55.33                                                                            6.11                                                                             4.53                                        159                                                                              C.sub.36 H.sub.36 ClN.sub.2 O.sub.4 SNa.4H.sub.2 O                                           58.40                                                                            6.34                                                                             4.01                                                                              58.31                                                                            6.26                                                                             3.81                                        174                                                                              C.sub.32 H.sub.32 ClN.sub.2 O.sub.5 SNa.0.5H.sub.2 O                                         61.58                                                                            5.33                                                                             4.49                                                                              61.83                                                                            5.27                                                                             4.39                                        176                                                                              C.sub.33 H.sub.34 ClN.sub.2 O.sub.4 SNa.0.5H.sub.2 O                                         63.71                                                                            5.67                                                                             4.50                                                                              63.89                                                                            5.62                                                                             4.46                                        180                                                                              C.sub.33 H.sub.35 ClN.sub.2 O.sub.5 S                                                        NMR data below                                              231                                                                              C.sub.32 H.sub.30 ClF.sub.3 N.sub.2 O.sub.4 S.sub.2 Na.sub.2.6H.sub.2         O              47.03                                                                            5.18                                                                             3.43                                                                              47.32                                                                            5.07                                                                             3.64                                        255                                                                              C.sub.31 H.sub.31 ClNO.sub.5 S.sub.2 Na                                                      NMR data below                                              309                                                                              C.sub.36 H.sub.40 ClN.sub.2 O.sub.3 SNa.4H.sub.2 O                                           60.79                                                                            6.80                                                                             3.94                                                                              60.65                                                                            6.86                                                                             4.12                                        344                                                                              C.sub.31 H.sub.28 ClNO.sub.2 SNa.1.5H.sub.2 O                                                58.62                                                                            4.88                                                                             2.20                                                                              58.75                                                                            5.09                                                                             2.15                                        355                                                                              C.sub.33 H.sub.32 ClN.sub.2 O.sub.3 SNa.1.5H.sub.2 O                                         63.70                                                                            5.67                                                                             4.50                                                                              63.80                                                                            5.66                                                                             4.35                                        361                                                                              C.sub.29 H.sub.27 ClNO.sub.5 S.sub.2 Na.H.sub.2 O                                            57.09                                                                            4.79                                                                             2.30                                                                              57.12                                                                            4.71                                                                             2.25                                        363                                                                              C.sub.32 H.sub.31 Cl.sub.2 N.sub.2 O.sub.3 SNa.2.5H.sub.2 O                                  58.01                                                                            5.48                                                                             4.23                                                                              57.92                                                                            5.31                                                                             3.98                                        378                                                                              C.sub.34 H.sub.37 ClN.sub.2 O.sub.3 S                                                        NMR data below                                              __________________________________________________________________________

EXAMPLE 65 (ACID)

¹ H NMR (CD₃ COCD₃) δ: 2.10 (2H, m), 2.30-2.60 (6H, m), 2.70 (3H, s),2.90 (3H, s), 3.90 (1H, t), 3.90 (3H, s), 5.30 (2H, s), 6.90 (1H, dd),7.00-7.40 (9H, m), 7.65 (1H, d), 7.85 (1H, d), 8.20 (1H, d).

EXAMPLE 97 (SODIUM SALT)

¹ H NMR (CD₃ COCD₃ :CD₃ SOCD₃) δ: 2.1-2.3 (4H, m), 2.4-2.7 (4H, m), 2.75(3H, s), 2.9 (3H, s), 3.95 (1H, t), 7.0-8.0 (14H, m), 8.38 (1H, d).

EXAMPLE 99 (ACID)

¹ H NMR (CD₃ COCD₃) δ: 2.2-2.4 (2H, m), 2.5-2.7 (4H, m), 2.7-3.0 (2H,m), 2.9 (3H, d), 4.0 (1H, t), 7.20-7.95 (14H, m), 8.05 (1H, br d), 8.35(1H, d).

EXAMPLE 180 (ACID)

¹ H NMR (CD₃ COCD₃) δ: 0.8 (3H, 2t, a mixture of diastereoisomers), 1.20(3H, t), 1.50 (2H, m), 2.05-3.0 (7H, m), 3.88 (1H, q), 4.10 (2H, 2q),5.40 (2H, s), 6.95-7.35 (6H, m), 7.52 (1H, br d), 7.59 (1H, dd), 7.75(2H, d), 8.00 (1H, d), 8.03 (1H, d), 8.40 (1H, d).

EXAMPLE 255 (SODIUM SALT)

¹ H NMR (CD₃ COCD₃) δ: 0.71 (3H, m, mixture of diasteromers), 1.46 (2H,m), 2.05-3.16 (10H, m), 3.91 (1H, 2t), 5.33 (2H, s), 6.83-7.05 (2H, m),7.16 (2H, m), 7.33 (2H, m), 7.53 (2H, m), 7.70 (1H, d), 7.91 (2H, t),8.00 (1H, br s), 8.33 (1H, d).

EXAMPLE 378 (ACID)

¹ H NMR (CD₃ COCD₃) δ: 0.82 (3H, m, mixture of diasteromers), 1.5 (2H,m), 2.06 (1H, m), 2.3-2.7 (6H, m), 2.85 (3H, 2s), 2.97 (3H, 2s), 3.14(2H, m), 3.78 (2H, m), 3.84 (1H, m), 7.1-7.3 (8H, m), 7.41 (1H, d), 7.48(1H, dd), 7.87 (1H, d), 8.0 (1H, s), 8.20 (1H, d).

EXAMPLES OF TABLE 3

The styrene-ester of Example 28, Step 1, was transformed to an amideusing Me₂ AlNMe₂ or Me₂ AlNHtBu as in Example 366, Step 10. It was thenconverted to the final product as in Example 28, Steps 2 and 3. In somecases, Quinolines 1-3 were used instead of2-(bromomethyl)-7-chloroquinoline.

                                      TABLE 3                                     __________________________________________________________________________                      Calculated                                                                              Found                                             Ex.                                                                              Formula        C  H  N   C  H  N                                           __________________________________________________________________________    62 C.sub.31 H.sub.31 N.sub.2 O.sub.4 SNa.1.5H.sub.2 O                                           64.46                                                                            5.93                                                                             4.85                                                                              64.40                                                                            6.04                                                                             4.78                                        63 C.sub.31 H.sub.29 Cl.sub.2 N.sub.2 O.sub.4 SNa.H.sub.2 O                                     58.40                                                                            4.90                                                                             4.39                                                                              58.94                                                                            4.71                                                                             4.36                                        64 C.sub.32 H.sub.33 N.sub.2 O.sub.6 S.sub.2 Na.2.3H.sub.2 O                                    57.35                                                                            5.66                                                                             4.18                                                                              57.20                                                                            5.77                                                                             4.01                                        67 C.sub.33 H.sub.34 ClN.sub.2 O.sub.4 SNa.3.2H.sub.2 O                                         59.09                                                                            6.07                                                                             4.18                                                                              58.99                                                                            6.11                                                                             3.96                                        __________________________________________________________________________

EXAMPLES OF TABLE 4

Starting with the lactones of Example 377, Step 3 and Example 229, Step8, and using the procedures of Example 366, Steps 10-13, the compoundsof Table 4 were obtained. Thiols 1, 4, 6, 14 and 15 and Me₂ AlNMe₂ andMe₂ AlNH₂ (at 65° C.) were used in their syntheses.

                                      TABLE 4                                     __________________________________________________________________________                      Calculated                                                                              Found                                             Ex.                                                                              Formula        C  H  N   C  H  N                                           __________________________________________________________________________    123                                                                              C.sub.31 H.sub.29 Cl.sub.2 N.sub.2 O.sub.4 SNa 1.5H.sub.2 O                                  57.58                                                                            4.94                                                                             4.33                                                                              57.37                                                                            4.97                                                                             4.21                                        124                                                                              C.sub.29 H.sub.25 Cl.sub.2 N.sub.2 O.sub.4 SNa 3H.sub.2 O                                    53.95                                                                            4.84                                                                             4.34                                                                              53.61                                                                            4.80                                                                             4.59                                        230                                                                              C.sub.30 H.sub.28 ClN.sub.2 O.sub.5 SNa 1.5H.sub.2 O                                         58.69                                                                            5.05                                                                             4.56                                                                              58.67                                                                            4.99                                                                             4.55                                        358                                                                              C.sub.33 H.sub.33 Cl.sub.2 N.sub.2 O.sub.4 SNa 4H.sub.2 O                                    55.07                                                                            5.74                                                                             3.84                                                                              55.32                                                                            5.73                                                                             3.88                                        359                                                                              C.sub.34 H.sub.34 Cl.sub.2 O.sub.4 SNa 2H.sub.2 O                                            61.76                                                                            5.79                                                                             4.24                                                                              61.85                                                                            5.85                                                                             4.11                                        360                                                                              C.sub.32 H.sub.32 Cl.sub.2 N.sub.2 O.sub.4 SNa 3H.sub.2 O                                    55.81                                                                            5.56                                                                             4.07                                                                              55.80                                                                            5.47                                                                             4.03                                        380                                                                              C.sub.30 H.sub.27 Cl.sub.2 N.sub.2 O.sub.4 SNa 3H.sub.2 O                                    54.63                                                                            5.04                                                                             4.25                                                                              54.85                                                                            4.94                                                                             4.33                                        __________________________________________________________________________

EXAMPLES OF TABLE 5 General procedure for mixed dithioacetal formationN,N-Dimethyl3-((acetylthio(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)methyl)thio)propanamide

To a solution of 3-(2-(7-chloro-2-quinolinyl)-ethenyl)benzaldehyde(10.74 g, 36.6 mmol) in 35 mL of TFA (trifluoroacetic acid) at r.t. wasadded thiolacetic acid (3.34 g, 3.14 mL, 43.9 mmol) followed byN,N-dimethyl-3-mercaptopropanamide (5.84 g, 43.9 mmol) in 5 mL of TFA.The mixture was stirred for 5 min, then poured into ice cold NH₄ OAcbuffer (500 mL). The aq layer was extracted with EtOAc (4×250 mL). Thecombined organic layers were washed with NH₄ OAc buffer (250 mL), brine(250 mL) and dried over MgSO₄. Plug filtration using EtOAc:hexane:MeOH10:10:1 gave 10.6 g (60% yield) of the title product.

Using the general procedure described above, the procedures of Examples14, 33 and 228, Thiols 1, 3, 16 and 17, Iodides 1 and 2, and2-(bromomethyl)benzonitrile, the compounds of Table 5 were synthesized.The tetrazoles (Examples 405 and 406) are obtained from the nitrilederivatives using the procedure of Example 40, Step 3.

                                      TABLE 5                                     __________________________________________________________________________                      Calculated                                                                              Found                                             Ex.                                                                              Formula        C  H  N   C  H  N                                           __________________________________________________________________________    386                                                                              C.sub.29 H.sub.22 ClNO.sub.4 S.sub.2 Na.sub.2 1.5H.sub.2 O                                   56.08                                                                            4.06                                                                             2.26                                                                              55.98                                                                            4.10                                                                             2.20                                        387                                                                              C.sub.29 H.sub.21 Cl.sub.2 NO.sub.4 S.sub.2 Na.sub.2 1.5H.sub.2                              53.14                                                                            3.69                                                                             2.14                                                                              52.92                                                                            3.95                                                                             2.42                                        390                                                                              C.sub.31 H.sub.29 ClN.sub.2 O.sub.3 S.sub.2 Na H.sub.2 O                                     60.33                                                                            4.90                                                                             4.54                                                                              60.18                                                                            4.97                                                                             4.58                                        391                                                                              C.sub.31 H.sub.28 Cl.sub.2 N.sub.2 O.sub.3 S.sub.2                                           NMR data below                                              405                                                                              C.sub.29 H.sub.24 ClN.sub.5 O.sub.2 S.sub.2                                406                                                                              C.sub.31 H.sub.29 ClN.sub.6 OS.sub.2                                       407                                                                              C.sub.34 H.sub.26 ClNO.sub.4 S.sub.2                                                         NMR data below                                              408                                                                              C.sub.34 H.sub.24 Cl.sub.3 NO.sub.4 S.sub.2                                                  NMR data below                                              409                                                                              C.sub.31 H.sub.29 ClN.sub.2 O.sub.3 S.sub.2                                410                                                                              C.sub.31 H.sub.28 Cl.sub.2 N.sub.2 O.sub.3 S.sub.2                                           NMR data below                                              __________________________________________________________________________

EXAMPLE 391 (ACID)

¹ H NMR (CDCl₃) δ: 2.60-3.15, (4H, m), 2.91 (3H, s), 3.03 (3H, s),4.10-4.35 (2H, m), 5.09 (1H, s), 7.30-8.05 (13H, m), 8.35 (1H, d).

EXAMPLE 407 (DIACID)

¹ H NMR (CDCl₃) δ: 4.10 (4H, m), 4.68 (1H, s), 6.95-8.10 (18H, m), 8.43(1H, d), 12.95 (2H, br s).

EXAMPLE 408 (DIACID)

¹ H NMR (CD₃ COCD₃) δ: 4.20 (4H, m), 4.74 (1H, s), 7.10-8.15 (16H, m),8.38 (1H, d).

EXAMPLE 410 (ACID)

¹ H NMR CDCl₃) δ: 2.56-2.95 (4H, m), (2.85 (3H, s), 3.10 (3H, s),3.70-3.96 (2H, m), 4.89 (1H, s), 7.10-7.75 (12H, m), 8.05-8.18 (2H, m).

EXAMPLES OF TABLE 6

Using the general procedure of Example 402, the compounds of Table 6were synthesized. Ketoesters 1-3, Thiols 1, 3 and 18, Iodides 1-3,2-(bromomethyl)nitrobenzene, and2-propyl-3-bromomethyl-2-pyridinecarboxylate (J. Med. Chem., 32,827(1989)) were used. In some cases the formation of the amide with Me₂AlNR₂ was avoided; in other cases, Me₂ AlNHtBu, Me₂ AlNH₂ )at 65° C.)were used. For Example 426, the nitrile was obtained with Me₂ AlNH₂ at80° C. and was transformed to the tetrazole (as in Example 40, Step 3).

                                      TABLE 6                                     __________________________________________________________________________                      Calculated                                                                              Found                                             Ex.                                                                              Formula        C  H  N   C  H  N                                           __________________________________________________________________________    385                                                                              C.sub.29 H.sub.22 Cl.sub.3 NO.sub.5 SNa.sub.2 1.5H.sub.2 O                                   51.53                                                                            3.73                                                                             --  51.24                                                                            3.95                                                                             --                                          389                                                                              C.sub.30 H.sub.27 Cl.sub.2 NO.sub.4 S                                                        NMR data below                                              392                                                                              C.sub.28 H.sub.33 ClN.sub.2 O.sub.5 SNa.sub.2 1.5H.sub.2 O                                   53.72                                                                            4.51                                                                             4.47                                                                              53.51                                                                            4.32                                                                             4.54                                        393                                                                              C.sub.30 H.sub.27 ClNO.sub.2 S                                                               NMR data below                                              394                                                                              C.sub.34 H.sub.35 ClNO.sub.2 S                                                               NMR data below                                              396                                                                              C.sub.30 H.sub.23 Cl.sub.2 NO.sub.4 SNa.sub.2 2.5H.sub.2 O                                   54.97                                                                            4.31                                                                             2.14                                                                              55.08                                                                            3.89                                                                             1.95                                        397                                                                              C.sub.32 H.sub.29 Cl.sub.2 N.sub.2 O.sub.3 SNa H.sub.2 O                                     60.66                                                                            4.93                                                                             4.42                                                                              60.50                                                                            4.51                                                                             4.16                                        398                                                                              C.sub.30 H.sub.25 Cl.sub.2 N.sub.2 O.sub.3 SNa 1.5H.sub.2 O                                  58.64                                                                            4.59                                                                             4.56                                                                              58.22                                                                            4.03                                                                             4.32                                        399                                                                              C.sub.30 H.sub.25 Cl.sub.2 N.sub.5 O.sub.2 S                                                 NMR data below                                              401                                                                              C.sub.34 H.sub.34 Cl.sub.2 N.sub.2 O.sub.3 S                                                 NMR data below                                              411                                                                              C.sub.29 H.sub.27 ClN.sub.2 O.sub.5 S                                                        NMR data below                                              412                                                                              C.sub.31 H.sub.28 ClNO.sub.5 S                                                               NMR data below                                              __________________________________________________________________________

EXAMPLE 389 (diacid)

¹ H NMR (CDCl₃) δ: 2.12 (2H, q), 2.42-2.58 (4H, m), 2.70-2.82 (1H, m),2.90-3.23 (3H, m), 3.32-3.50 (2H, m), 3.80 (1H, t), 6.55 (1H, d),6.94-7.17 (2H, m), 7.18 (1H, m), 7.32-7.48 (4H, m), 7.72 (1H, d), 7.90(1H, d), 8.06 (1H, d), 8.18 (1H, d).

EXAMPLE 393 (acid)

¹ H NMR (CD₃ COCD₃) δ: 2.28 (2H, m), 2.50 (2H, m), 2.63 (2H, m),2.75-3.00 (2H, m), 4.02 (1H, dd), 6.86 (1H, br s), 7.20-7.65 (10H, m),7.75-8.05 (5H, m), 8.32 (1H, d).

EXAMPLE 394 (acid)

¹ H NMR (CD₃ COCD₃) δ: 1.41 (9H, s), 2.25 (2H, m), 2.48 (2H, m), 2.60(2H, m), 2.68-2.93 (2H, m), 4.02 (1H, m), 6.93 (1H, br s), 7.20-7.30(4H, m), 7.48-7.70 (5H, m), 7.76-8.05 (5H, m), 8.33 (1H, d).

EXAMPLE 399 (acid)

¹ H NMR (CD₃ COCD₃) δ: 2.22 (2H, t), 2.45-2.5 (1H, m), 2.5 (1H, d),2.55-2.62 (1H, m), 2.6 (1H, d), 2.9-3.0 (1H, m), 3.0-3.1 (1H, m),4.0-4.1 (1H, m), 7.38 (2H, t), 7.45-7.6 (4H, m), 7.62 (1H, d), 7.75 (1H,s), 7.8-8.0 (4H, m), 8.05 (1H, s), 8.35 (1H, d).

EXAMPLE 401 (acid)

¹ H NMR (CD₃ COCD₃) δ: 1.42 (9H, s), 2.25 (2H, m), 2.50 (2H, m), 2.60(2H, m), 2.79 (2H, m), 4.02 (1H, t), 7.12 (1H, s, NH), 7.28 (3H, m),7.41-7.55 (4H, m), 7.65 (1H, m), 7.79-8.03 (5H, m), 8.35 (1H, d).

EXAMPLE 411 (acid)

¹ H NMR (CD₃ COCD₃) δ: 1.05-1.10 (3H, 2d, mixture of diasteromers),2.07-3.00 (7H, m), 3.96 (1H, 2t), 5.43 (2H, s), 6.96 (2H, m), 7.15-7.30(2H, m), 7.45 (2H, m), 7.60 (2H, m), 7.75 (1H, d), 7.90 (1H, d), 8.00(2H, m), 8.40 (1H, d).

EXAMPLE 412 (diacid)

¹ H NMR (CD₃ COCD₃) δ: 2.25 (2H, m), 2.72 (2H, m), 2.95 (1H, m), 3.02(1H, m), 3.34-3.37 (3H, 2s, mixture of diastereoisomers), 3.88 (1H, m),4.17 (1H, m), 7.05-7.70 (9H, m), 7.70-8.05 (5H, m), 8.35 (1H, d).

    TABLE 7      The following compounds (formula I") are within the scope of the     invention:      ##STR18##      I"      Ex Y A B     97 CHCH S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2  98 CH.sub.2CH.sub.2 S(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)CON(CH.sub.3).sub.2  99 CHCH     S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)CONHCH.sub.3 100     CH.sub.2 O SCH.sub.2 C(CH.sub.3).sub.2 COOH (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 101 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CON(CH.sub.3).sub.2 102     CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.2 CH.sub.3).sub.2 103 CH.sub.2CH.sub.2 SCH.sub.2     C(CH.sub.3).sub.2 COOH (CH.sub.2).sub.2 (1,2-Phe)CON(CH.sub.3).sub.2 104 C     H.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-Phe)CONHCH.sub.2 CH(CH.sub.3).sub.2 105 CH.sub.2 O SCH.sub.2     C(CH.sub.2 CH.sub.3).sub.2 COOH (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 106 CH.sub.2 O SCH.sub.2 C(CH.sub.2     CH.sub.2)COOH (CH.sub.2).sub.2 (1,2-Phe)CON(CH.sub.3).sub.2 107 CH.sub.2     O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.2).sub.4 108 CH.sub.2CH.sub.2 SCH.sub.2 C(CH.sub.2     CH.sub.2)COOH (CH.sub.2).sub.2 (1,2-Phe)CON(CH.sub.3).sub.2 109 CH.sub.2     O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4-ClPhe))CON(CH.sub.3).sub.2 110 CH.sub.2 O S(CH.sub.2).sub.2     CN.sub.4      H (CH.sub.2).sub.2 (1,2-Phe)CON(CH.sub.3).sub.2 111 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.3)CN.sub.4 H (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 112 CH(CH.sub.2)CH S(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)CON(CH.sub.3).sub.2 113 CH.sub.2 O     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 114 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CONH.sub.2 115 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)CONHCH.sub.3 116 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)COOH 117 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)COOH 118     CH.sub.2 O S(CH.sub.2).sub.3 COOH (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 119 CH.sub.2 O SCH.sub.2 CH(CH.sub.2     CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CONHCH.sub.2 CH.sub.3 120     CH.sub. 2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)CONH.sub.2 121 CH.sub.2 O SCH.sub.2 CH((CH.sub.2).sub.2     CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CONHCH.sub.2 CH.sub.3 122     CH.sub.2 O SCH.sub.2 CH((CH.sub.2).sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)CONH.sub.2 123 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-(4-ClPhe))CONH.sub.2 124 CH.sub.2      O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4-ClPhe))CONH.sub.2 125 CH.sub.2 O SCH.sub.2 C(CH.sub.3).sub.2     COOH (CH.sub.2).sub.2 (1,2-(4-ClPhe))CONH.sub.2 126 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CONH.sub.2     127 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,3-Phe)CN.sub.4 H 128 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,3-Phe)SO.sub.2 N(CH.sub.3).sub. 2 129 CH.sub.2 O     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,3-Phe)CON(CH.sub.3).sub.2 130 CH.sub.2 O SCH.sub.2 CH(CH.sub.2     CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)NHCO.sub.2 CH.sub.2 CH.sub.3 131 C     H.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,3-Phe)N(CH.sub.3)CO.sub.2 CH.sub.3 132 CH.sub.2 O SCH.sub.2      CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)NHCO.sub.2 (4-ClPh)     133 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,3-Phe)CN 134 CH.sub.2 O SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)COCF.sub.3 135 CH.sub.2 O     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)COPh 136     CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,3-Phe)SO.sub.2 Ph 137 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (     CH.sub.2).sub.2 (1,3-Phe)SO.sub. 2 CF.sub.3 138 CH.sub.2 O SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,3-Phe)NHCOC(CH.sub.3).sub.3 139 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,3-Phe)COOH 140 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,3-Phe)CN.sub.4 H 141 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)SO.sub.2      N(CH.sub.3).sub.2 142 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)CON(CH.sub.3).sub.2 143         C     CH.sub.2H.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,3-Phe)NHCO.sub.2 CH.sub.2 CH.sub.3 144 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)N(CH.sub.3)CO.sub.2     CH.sub.3 145 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,3-Phe)NHCO.sub.2 (4-ClPh) 146 CH.sub.2 CH.sub.2     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)CN 147     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,3-Phe)COCF.sub.3 148 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)COPh 149 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)SO.sub.2     Ph 150 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)SO.sub.2      CF.sub.3 151 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)CN.sub.4 H 152 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CONHSO.sub.2     (4-CH.sub.3Ph) 153 CH.sub.2 O SCH.sub.2 C(CH.sub.3).sub.2      COOH (CH.sub.2).sub.2 (1,2-Phe)CONH.sub.2 154 CH.sub.2      O S(CH.sub.2).sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CONH.sub.2 155 CH.sub. 2CH.sub.2 SCH.sub.2 CH(CH.sub.2     CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CN.sub.4 CH.sub.3 156 CH.sub.2 O S     CH.sub.2 C(CH.sub.3).sub.2 COOH (CH.sub.2).sub.2 (1,2-Phe)CN.sub.4 H 157 C     H.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CONHCH.sub.3 158 CH.sub.2 O SCH.sub.2 C(CH.sub.3).sub.2 COOH     (CH.sub.2).sub.2 (1,2-Phe)CN.sub.4 H 159 CH.sub.2 O SCH.sub.2      CH((CH.sub.2).sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 160 CH.sub.2 O SCH.sub.2 CH(CH.sub.2     CH.sub.3)CON(CH.sub.3).sub.2 (CH.sub.2).sub.2(1,2-Phe)COOH 162 CH.sub.2     O SCH.sub.2 CH(CH.sub.2      CH.sub.3)CON(CH.sub.3).sub.2 (CH.sub.2).sub.2(1,2-Phe)CN.sub.4 H 163     CH.sub.2 O SCH.sub.2 CH(CH.sub.2      CH.sub.3)CON(CH.sub.3).sub.2 (CH.sub.2).sub.2(1,2-Phe)CONH(SO.sub.2 Ph)     164 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)CON(CH.sub.3 ).sub.2 (     CH.sub.2).sub.2(1,2-Phe)COOH 165 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2     CH.sub.3)CON(CH.sub.3).sub.2 (CH.sub.2).sub.2(1,2-Phe)CN.sub.4 H 166     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)CON(CH.sub.3).sub.2     (CH.sub.2).sub.2(1,2-Phe)CONH(SO.sub.2 Ph) 167 CH.sub.2 O SCH.sub.2     CH(CH.sub.2      CH.sub.3)CON(CH.sub.3).sub.2 (CH.sub.2).sub.2(1,2-(4-ClPhe))COOH 168     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)CON(CH.sub.3).sub.2     (CH.sub.2).sub.2 (1,2-(4-ClPhe))COOH 169 CH.sub.2 O S(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH.sub.3 170 CH.sub.2 O     S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2     CH.sub.2 CH.sub.3 171 CH.sub.2CH.sub.2 S(CH.sub.2).sub.2 CO.sub.2 H     (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH.sub.3 172 CH.sub.2CH.sub.2     S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2     CH.sub.2 CH.sub.3 173 CH.sub.2 O SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH.sub.3 174     CH.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)NHCO.sub.2 CH.sub.2 CH.sub.3 175 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH.sub.3 176     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)NHCO.sub.2 CH.sub.2 CH.sub.3 177 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH.sub.3     178 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH.sub.2 CH.sub.3     179 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)NHCO.sub.2 CH.sub.3 180 CH.sub.2 O SCH.sub.2 CH(CH.sub.2     CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH.sub.2 CH.sub.3 181 C     H.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-Phe)NHCO.sub.2 CH(CH.sub.2).sub.4 182 CH.sub.2 O S(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 Ph 183 CH.sub.2CH.sub.2     S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2     CH(CH.sub.2).sub.4 184 CH.sub.2CH.sub.2 S(CH.sub.2).sub.2 CO.sub.2 H     (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 Ph 185 CH.sub.2 O SCH.sub.2     CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH(CH.sub.2).sub.4     186 CH.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)NHCO.sub.2 Ph 187 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2      CH(CH.sub.2).sub.4 188 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 Ph 189 CH.sub.2 O SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2      CH(CH.sub.2).sub.4 190 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 Ph 191 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2      CH(CH.sub.2).sub.4 192 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 Ph 193 CH.sub.2 O     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2     C(CH.sub.3).sub.3 194 CH.sub.2 O SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)COOH 195 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)COOH 196     CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CN.sub.4 H 197 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)CN.sub.4 H 198 CH.sub.2 O SCH.sub.2      CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CONHSO.sub.2 Ph 199 C     H.sub.2 O  SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CONHSO.sub.2 CF.sub.3 200 CH.sub.2 O SCH.sub.2 CH(CH.sub.2     CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CONHSO.sub.2 CH.sub.3 201     CH.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CONHSO.sub.2 Ph 202 CH.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)CONHSO.sub.2 CF.sub.3 203 CH.sub.2 O SCH.sub.2     CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CONHSO.sub.2 CH.sub.3 204     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CONHSO.sub.2 Ph 205 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CONHSO.sub.2 CF.sub.3 206     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CONHSO.sub.2 CH.sub.3 207 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CONHSO.sub.2 Ph 208 C     H.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3 )COOH (CH.sub.2).sub.2     (1,2-Phe)CONHSO.sub.2 CF.sub.3 209 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CONHSO.sub.2     CH.sub.3 210 CH.sub.2 O SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-(3-ClPh))COOH 211 CH.sub.2 O     SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-(3-ClPh))COOH 212     CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(3-ClPh))COOH 213 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-(3-ClPh))COOH 214 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-(3-ClPh))COOH 215     CH.sub.2CH.sub.2 S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2           P      (1,2-(3-Clh))COOH 216 CH.sub.2 O SCH.sub.2      CH(OCH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CON(CH.sub.3).sub.2 217     CH.sub.2CH.sub.2 SCH.sub.2 CH(OCH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 218  CH.sub.2 O SCH.sub.2      C(CH.sub.3)(OCH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 219 CH.sub.2CH.sub.2 SCH.sub.2      C(CH.sub.3)(OCH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 220 CH.sub.2 O SCH.sub.2 CH(OCH.sub.3)COOH (     CH.sub.2).sub.2 (1,2,-Phe)COOH 221 CH.sub.2CH.sub.2 SCH.sub.2      C(CH.sub.3)(OCH.sub.3)COOH (CH.sub.2).sub.2 (1,2,-Phe)COOH 222 CH.sub.2     O SCH.sub.2 CH(OCH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CN.sub.4 H 223     CH.sub.2CH.sub.2 SCH.sub.2 CH(OCH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CN.sub.4 H 224 CH.sub.2 O SCH.sub.2 C(CH.sub.3)(OCH.sub.3)COOH (     CH.sub.2).sub.2 (1,2-Phe)CN.sub.4 H 225 CH.sub.2CH.sub.2 SCH.sub.2     C(CH.sub.3)(OCH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CN.sub.4 H 226     CH.sub.2 O SCH.sub.2 CH(OCH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)NHCO.sub.2 CH.sub.2 CH.sub.3 227 CH.sub.2CH.sub.2 SCH.sub.2     C(CH.sub.3)(OCH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH.sub.2     CH.sub.3 228 CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2     (1,2-Phe)CON(CH.sub.3).sub.2 229 CH.sub.2 O SCH.sub.2 CH(OCH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)CONH.sub.2 230 CH.sub.2 O SCH.sub.2      C(CH.sub.3)(OH)COOH (CH.sub.2).sub.2      (1,2-Phe)CONH.sub.2 231 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NHSO.sub.2 CF.sub.3 232     CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)COCF.sub.3 233 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)COPh 234 CH.sub.2 O SCH.sub.2 CH(CH.sub.2     CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CO(2-MePh) 235 CH.sub.2 O     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CHO 236     CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CH.sub.2 OH 237 CH.sub.2 O SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)COCF.sub.3 238 CH.sub.2 O     SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)COPh 239 CH.sub.2 O S     CH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CO(2-MePh) 240     CH.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CHO 241     CH.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CH.sub.2     OH 242 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)COCF.sub.3 243 CH.sub.2CH.sub.2 S     CH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)COPh 244     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)CO(2-MePh) 245 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CHO 246 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CH.sub.2     OH 247 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)COCF.sub.3 248 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)COPh 249 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)CO(2-MePh) 250 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)CHO 251 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CH.sub.2 OH 252 CH.sub.2 O     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2     Ph 253 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)SOPh 254 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 CF.sub.3 255 CH.sub.2 O SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 CH.sub.3     256 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)SOCH.sub.3 257 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)NO.sub.2 258 CH.sub.2 O SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 Ph 259 CH.sub.2 O     SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SOPh 260 CH.sub.2 O S     CH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 CF.sub.3     261 CH.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)SO.sub.2 CH.sub.3 262 CH.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)SOCH.sub.3 263 CH.sub.2 O SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)S(4-ClPh) 264 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2      Ph 265 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SOPh 266 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2     CF.sub.3 267 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 CH.sub.3 268 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SOCH.sub.3     269 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)S(4-ClPh) 270 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 Ph 271     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)SOPh 272 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 CF.sub.3 273     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)SO.sub.2 CH.sub.3 274 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)SOCH.sub.3 275 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)S(4-ClPh) 276 CH.sub.2 O SCH.sub.2 CH(CH.sub.2     CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2      NH.sub.2 277 CH.sub.2CH.sub. 2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 NH.sub.2 278 CH.sub.2 O SCH.sub.2     CH(CH(CH.sub.2 CH.sub.2)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 NH.sub.2     279 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH(CH.sub.2      CH.sub.2)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 NH.sub.2 280 CH.sub.2     O SCH.sub.2 CH(CH.sub.2).sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)SO.sub.2 NH.sub.2 281 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.2).sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2     NH.sub.2 282 CH.sub.2 O SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 N(CH.sub.3).sub.2 283     CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)SO.sub.2 N(CH.sub.2 CF.sub.3).sub.2 284 CH.sub.2 O SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 NH(4-ClPh)     285 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)SO.sub.2 NHCH.sub.2 (4-ClPh) 286 CH.sub.2 O SCH.sub.2      CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2      N(CH.sub.3).sub.2 287 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 N(CH.sub.2 CF.sub.3).sub.2 288     CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)SO.sub.2 NH(4-ClPh) 289 CH.sub.2 O SCH.sub.2 CH(CH.sub.2     CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 NHCH.sub.2 (4-ClPh) 290 C     H.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)SO.sub.2 N(CH.sub.3).sub.2 291 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 N(CH.sub.2      CF.sub.3).sub.2 292 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 NH(4-ClPh) 293 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 NHCH.sub.2     (4-ClPh) 294 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 N(CH.sub.3).sub.2     295 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)SO.sub.2 N(CH.sub.2 CF.sub.3).sub.2 296 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)SO.sub.2 NH(4-ClPh)     297 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)SO.sub.2 NHCH.sub.2 (4-ClPh) 298 CH.sub.2 O SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NH(COPh) 299 CH.sub.2 O     SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)N(CH.sub.3)COPh 300 C     H.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)NH(COC(CH.sub.3).sub.3) 301 CH.sub.2 O SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)N(CH.sub.3)COC(CH.sub.3).sub.3 302 CH.sub.2 O SCH.sub.2     CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NH(COCH.sub.2 Ph) 303     CH.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)NH(SO.sub.2 Ph) 304 CH.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)N(CH.sub.3)SO.sub.2 Ph 305 CH.sub.2      O SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NH(SO.sub.2     CF.sub.3) 306 CH.sub.2 O SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)N(CH.sub.3)SO.sub.2 CF.sub.3 307 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NH(COPh) 308         C     CH.sub.2H.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)N(CH.sub.3)COPh 309 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2     CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NH(COC(CH.sub.3).sub.3) 310     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)N(CH.sub.3)COC(CH.sub.3).sub.3) 311 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NH(COCH.sub. 2 Ph)     312 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NH(SO.sub.2      Ph) 313 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)N(CH.sub.3)SO.sub.2 Ph 314     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)NH(SO.sub.2 CF.sub.3) 315 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)N(CH.sub.3)SO.sub.2     CF.sub.3 316 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)NH(COPh) 317 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)N(CH.sub.3)COPh 318 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NH(COC(CH.sub.3).sub.3) 319     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)N(CH.sub.3)COC(CH.sub.3).sub.3 320 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)NH(COCH.sub.2 Ph) 321         C     CH.sub.2H.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)NH(SO.sub.2 Ph) 322 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)N(CH.sub.3)SO.sub.2 Ph 323     CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)NH(SO.sub.2 CF.sub.3) 324 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)N(CH.sub.3)SO.sub.2 CF.sub.3     325 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)N(CH.sub.3)CO.sub.2 CH.sub.2 CH.sub.3 326 CH.sub.2 O SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)N(CH.sub.3)CO.sub.2     (4-ClPh) 327 CH.sub.2 O SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)OC(O)N(CH.sub.3).sub.2 328     CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2      (1,2-Phe)OC(O)N(CH.sub.2 CF.sub.3).sub.2 329 CH.sub.2 O SCH.sub.2     CH(CH.sub.2 CH.sub.3 )COOH (CH.sub.2).sub.2 (1,2-Phe)OC(O)NH(CH.sub.2     (4-ClPh) 330 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)N(CH.sub.3)CO.sub.2 CH.sub.2     CH.sub.3 331 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)N(CH.sub.3)CO.sub.2 (4-ClPh)     332 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH (CH.sub.2).sub.2     (1,2-Phe)OC(O)N(CH.sub.3).sub.2 333 CH.sub.2CH.sub.2 SCH.sub.2      CH(CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)OC(O)N(CH.sub.2      CF.sub.3).sub.2 334 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.3)COOH     (CH.sub.2).sub.2 (1,2-Phe)OC(O)NH(CH.sub.2 (4-ClPh) 335 CH.sub.2 O     SCH.sub.2 CH(CH.sub.2 (4-ClPh))COOH (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 336 CH.sub.2 O SCH.sub.2 CH(CH.sub.2     (4-ClPh))COOH (CH.sub.2).sub.2 (1,2-Phe)COOH 337 CH.sub.2 O SCH.sub.2     CH(CH.sub.2 (4-ClPh))COOH (CH.sub.2).sub.2 (1,2-Phe)CN.sub.4 H 338     CH.sub.2 O SCH.sub.2 CH(CH.sub.2 (4-ClPh))COOH (CH.sub.2).sub.2      (1,2-Phe)NHCO.sub.2 CH.sub.2 CH.sub.3 339 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.2 (4-ClPh))COOH (CH.sub.2).sub.2 (1,2-Phe)CON(CH.sub.3).sub.2     340 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      (4-ClPh))COOH (CH.sub.2).sub.2 (1,2-Phe)COOH 341 CH.sub.2CH.sub.2     SCH.sub.2 CH(CH.sub.2 (4-ClPh))COOH (CH.sub.2).sub.2 (1,2-Phe)CN.sub.4 H     342 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      (4-ClPh))COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH.sub.2 CH.sub.3     343 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)CN 344 CH.sub.2 O SCH.sub.2     CH(CH.sub.2 CH.sub.3)COOH (CH.sub.2).sub.2 (1,2-Phe)COOH 345 CH.sub.2 O     SCH.sub.2 CH(CH.sub.2 CH(CH.sub.2).sub.2)COOH (CH.sub.2).sub.2      (1,2-Phe)CONHCH.sub.3 346 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2     CH(CH.sub.2).sub.2)COOH (CH.sub.2).sub.2 (1,2-Phe)CONHCH.sub.3 347     CH.sub.2 O SCH.sub.2 CH(CH.sub.2      CH(CH.sub.2).sub.2)COOH (CH.sub.2).sub.2      (1,2,Phe)COOH 348 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH(CH.sub.2).sub.2)COOH (CH.sub.2).sub.2 (1,2,Phe)COOH 349 CH.sub.2 O     SCH.sub.2 CH(CH.sub.2 CH(CH.sub.2).sub.2)COOH (CH.sub.2).sub.2      (1,2-Phe)CN.sub.4 H 350 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH(CH.sub.2).sub.2)COOH (CH.sub.2).sub.2 (1,2-Phe)CN.sub.4 H 351     CH.sub.2 O SCH.sub.2 CH(CH.sub.2      CH(CH.sub.2).sub.2)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH.sub.2     CH.sub.3 352 CH.sub.2CH.sub.2 SCH.sub.2 CH(CH.sub.2      CH(CH.sub.2).sub.2)COOH (CH.sub.2).sub.2 (1,2-Phe)NHCO.sub.2 CH.sub.2     CH.sub.3 353 CH.sub.2 O SCH.sub.2 CH(CH.sub.2      CH.sub.3)COOH (CH.sub.2).sub.2 (1,3-Phe)COOH 354 CH.sub.2 O SCH.sub.2     CH(CH.sub.2 CH.sub.3)CONH.sub.2 (CH.sub.2).sub.2 (1,2-Phe)CO.sub.2 H 355 C     H(CH.sub.2)CH SCH.sub.2 CH(CH.sub.2 CH.sub.3)CO.sub.2      H  (CH.sub.2).sub.2 (1,2-Phe)CONH.sub.2 356 CH.sub.2      O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4-ClPhe))CONHCH.sub.3 357 CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H (     CH.sub.2).sub.2 (1,2-(4-ClPhe))CON(CH.sub.3)CH.sub.2 OH 358 CH.sub.2 O     SCH.sub.2 CH(CH.sub.2 CH.sub.3)CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4-ClPhe))CON(CH.sub.3).sub.2 359 CH.sub.2 O SCH.sub.2      CH(CHCH.sub.2 CH.sub.2)CO.sub.2 H (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 360 CH.sub.2 O SCH.sub.2      CH(CH.sub.3)CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4-ClPhe))CON(CH.sub.3).sub.2 361 CH.sub.2 O S(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)S(O).sub.2 CH.sub.3 362 CH.sub.2 O     S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,2-(4-ClPhe))CO.sub.2 H     363 CH.sub.2CH.sub.2 S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2     (1,2-(4-ClPhe))CON(CH.sub.3).sub.2 364 CH.sub.2 O SCH.sub.2      CH(CH.sub.3)CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)C(NOH)CH.sub.3 365     CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4-ClPhe))CON(CH.sub.3).sub.2 (+) 366 CH.sub.2 O S(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-(4-ClPhe))CON(CH.sub.3).sub.2 (-) 367     CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4-ClPhe))NHCO.sub.2 CH.sub.2 CH.sub.3 368 CH.sub.2      O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(6-ClPhe))CON(CH.sub.3).sub.2 369 CH.sub.2 O S(O)(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-(4-ClPhe))CON(CH.sub.3).sub.2 370     CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(3-ClPhe))CON(CH.sub.3).sub.2 371 CH.sub.2 O S(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-(4-ClPhe))CONH(CH.sub.2).sub.2 OH 372     CH.sub.2 O  SCH.sub.2 CH(CH.sub.3)CO.sub.2 H (CH.sub.2).sub.2      (1,2-Phe)CN.sub.4 H 373 CH.sub.2 O SCH.sub.2 CH(CH.sub.3)CO.sub.2 H     (CH.sub.2).sub.2 (1,2-Phe)CONH.sub.2 374 CH.sub.2 O S(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)CON(CH.sub.3).sub.2 (+) 375     CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 (-) 376 CH.sub.2 O S(CH.sub.2).sub.2 COOH     (CH.sub.2).sub.2 (1,2-(4-BrPhe))CO.sub.2 H 377 CH.sub.2      O SCH(CH.sub.3)CH.sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4-ClPhe))CON(CH.sub.3).sub.2 378 CH.sub.2CH.sub.2 SCH.sub.2     CH(CH.sub.2 CH.sub.3)CO.sub.2 H (CH.sub.2).sub.2      (1,2-Phe)CON(CH.sub.3).sub.2 379 CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2     H (CH.sub.2).sub.2 (2,5-Fur)CON(CH.sub.3).sub.2 * 380 CH.sub.2 O     SCH.sub.2 CH(CH.sub.3)CO.sub.2 H (CH.sub.2 ).sub.2      (1,2-(4-ClPhe))CONH.sub.2 381 CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H     (CH.sub.2).sub.2 (1,2-(4-ClPhe))NHCOCH.sub.3 382 CH.sub.2      O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)CONHS(O).sub.2     CH.sub.3 383 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)CO.sub.2 H     (CH.sub.2).sub.2 (1,2-(4-ClPhe))CO.sub.2 H 384 CH.sub.2 O SCH.sub.2     CH(CH.sub.3)CO.sub.2 H (CH.sub.2).sub.2 (1,2-(4-ClPhe))CO.sub.2 H 385     CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4,5-diClPhe))CO.sub.2 H 386 CHCH S(CH.sub.2).sub.2 CO.sub.2 H     SCH.sub.2 (1,2-Phe)CO.sub.2 H 387 CHCH S(CH.sub.2).sub.2 CO.sub.2 H     SCH.sub.2 (1,2-(4-ClPhe))CO.sub.2 H 388 CH.sub.2 O SCH.sub.2      CH(OCH.sub.3)CO.sub.2 H (CH.sub.2).sub.2 (1,2-(4-ClPhe))CO.sub.2 H 389     CH.sub.2CH.sub.2 S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub. 2).sub.2      (1,2-(4-ClPhe))CO.sub.2 H 390 CHCH S(CH.sub.2).sub.2      CON(CH.sub.3).sub.2 SCH.sub.2 (1,2-Phe)CO.sub.2      H 391 CHCH S(CH.sub.2).sub.2 CON(CH.sub.3).sub.2 SCH.sub.2      (1,2-(4-ClPhe))CO.sub.2 H 392 CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H     (CH.sub.2).sub.2 (3,2-Pye)CO.sub.2 H 393 CHCH S(CH.sub.2).sub.2 CO.sub.2     H (CH.sub.2).sub.2 (1,2-Phe)CONH.sub.2 394 CHCH S(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)CONHC(CH.sub.3).sub.3 395 CH.sub.2     O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,2-(4-PhPhe))CO.sub.2     H 396 CHCH S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4-ClPhe))CO.sub.2 H 397 CHCH S(CH.sub.2).sub.2      CON(CH.sub.3).sub.2 (CH.sub.2).sub.2 (1,2-(4-ClPhe))CO.sub.2 H 398 CHCH S     (CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,2-(4-ClPhe))CONH.sub. 2     399 CHCH S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4-ClPhe)CN.sub.4 H 400 CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H     (CH.sub.2).sub.2 (3,2-Pye)CON(CH.sub.3).sub.2 401 CHCH S(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-(4-ClPhe)CONHC(CH.sub.3).sub.3 402 CHCH S     (CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-(4-ClPhe)CON(CH.sub.3).sub.2 403 CH.sub.2 O S(CH.sub.2).sub.2     CO.sub.2 H (CH.sub.2).sub.2 (1,2-(4-ClPhe)CN.sub.4 H 404 CH.sub.2 O     SCH.sub.2 CH(CH.sub.3)CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)CN 405 CHCH     S(CH.sub.2).sub.2 CO.sub.2 H SCH.sub.2 (1,2-Phe)CN.sub.4 H 406 CHCH     S(CH.sub.2).sub.2 CON(CH.sub.3).sub.2 SCH.sub.2 (1,2-Phe)CN.sub.4 H 407     CHCH SCH.sub.2 (1,2-Phe)CO.sub.2 H SCH.sub.2 (1,2-Phe)CO.sub.2 H 408     CHCH SCH.sub.2 (1,2-(4-Cl Phe))CO.sub.2 H SCH.sub.2      (1,2-(4-ClPhe))CO.sub.2 H 409 CHCH S(CH.sub.2).sub.2 CO.sub.2 H     SCH.sub.2 (1,2-Phe)CON(CH.sub.3).sub.2 410 CHCH S(CH.sub.2).sub.2     CO.sub.2 H SCH.sub.2 (1,2-(4-ClPhe))CON(CH.sub.3).sub.2 411 CH.sub.2 O     SCH.sub.2 CH(CH.sub.3)CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)NO.sub.2 412     CHCH SCH.sub.2 CH(OCH.sub.3)CO.sub.2 H (CH.sub.2).sub.2      (1,2-Phe)CO.sub.2 H 413 CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H     (CH.sub.2).sub.2 (1,4-(2-(CH.sub.3 O)Phe))CO.sub.2 H 414 CHCH SCH.sub.2     CH(CH.sub.3)CO.sub.2 H (CH.sub.2).sub.2 (1,4-(2-(CH.sub.3      O)Phe))CO.sub.2 H 415 CH.sub.2 CH.sub.2 S(CH.sub.2).sub.2 CO.sub.2 H     (CH.sub.2).sub.2 (1,2-Phe)CH(CH.sub.3)CO.sub.2 H 416 CH.sub.2      O S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1,2-Phe)CH(CH.sub.3)NHCO.sub.2 CH.sub.2 CH.sub.3 417 CHCH  SCH.sub.2     CH(CH.sub.3)CO.sub.2 H (CH.sub.2).sub.2 (1,3-Phe)C(CH.sub.3).sub.2     CO.sub.2 H 418 CH.sub.2 O SCH.sub.2 CH(CH.sub.2 CH.sub.3)CO.sub.2 H     (CH.sub.2).sub.2 (1,2-Phe)C(CH.sub.3).sub.2 CONHS(O).sub.2 CH.sub.3 419     CHCH S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2      (1-3,Phe)CH(CH.sub.3)CN.sub.4 H 420 CHCH S(CH.sub.2).sub.2 CO.sub.2 H     (CH.sub.2).sub.2 (1,3-Phe)CH(CH.sub.3)CON(CH.sub.3).sub.2 421 CH.sub.2 O S     (CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)CH.sub.2      S(O).sub.2 CF.sub.3 422 CH.sub.2 O S(CH.sub.2).sub.2 CO.sub.2 H     (CH.sub.2).sub.2 (1,2-Phe)C(CH.sub.3).sub.2 NHCOC(CH.sub.3).sub.3 423     CHCH S(CH.sub.2).sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)CH.sub.2     S(O)CH.sub.2     *Fur = furanediyl

What is claimed is:
 1. A compound of the formula: ##STR19## wherein: R¹is H, halogen, C₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₂ -C₈ alkynyl, --CF₃,--SR², --S(O)R², --S(O)₂ R², --OR³, --COOR³, --(C═O)R³, --C(OH)R³ R³,--CN, --N₃, substituted or unsubstituted phenyl, substituted orunsubstituted benzyl, substituted or unsubstituted 2-phenethyl, orsubstituted or unsubstituted pyridyl;R² is C₁ -C₈ alkyl, C₂ -C₈ alkenyl,C₂ -C₈ alkynyl, --CF₃, substituted or unsubstituted phenyl, substitutedor unsubstituted benzyl, or substituted or unsubstituted 2-phenethyl; R³is H or R² ; R⁴ is H, halogen, --NO₂, --CN, --OR³, --SR³, NR³ R³, or C₁-C₈ alkyl; R⁵ is H, halogen, --N₃, --CN, --SR², --NR³ R³, --OR³, C₁ -C₈alkyl, --(C═O)R³ ; R⁶ is --CH₂ CONR¹² R¹² ; R⁷ is H or C₁ -C₄ alkyl; R¹⁰is --SR¹¹, --OR¹², or --NR¹² R¹² ; R¹¹ is C₁ -C₆ alkyl, --(C═O)R¹⁴,unsubstituted phenyl, or unsubstituted benzyl; R¹² is H or R¹¹ ; R¹³ isC₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₂ -C₈ alkynyl, --CF₃, or unsubstitutedphenyl, benzyl, or 2-phenethyl; R¹⁴ is H or R¹³ ; R¹⁵ is R³ or halogen;R¹⁶ is H, C₁ -C₄ alkyl, or OH; R¹⁷ is C₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₂-C₈ alkynyl, or substituted or unsubstituted phenyl, benzyl, or2-phenethyl; R¹⁸ is C₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₂ -C₈ alkynyl, --CF₃,or substituted or unsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁹ isC₄ -C₈ alkyl, C₂ -C₈ alkenyl, C₂ -C₈ alkynyl, --CF₃, or unsubstitutedphenyl, benzyl, or 2-phenethyl; m and m' are independently 0-8; n and n'are independently 0 or 1 but not both 0; p and p' are independently 0-8;m+n+p is 1-10 when X² is O, S, S(O), or S(O)₂ ; m+n+p is 0-10 when X² isCR³ R¹⁶ ; m'+n'+p' is 1-10 when X³ is O, S, S(O), or S(O)₂ ; m'+n'+p' is0-10 when X³ is CR³ R¹⁶ ; r is 0 or 1 when Z¹ is HET (--R³, --R⁵); r is1 when Z¹ is --CONR³ ; r' is 0 or 1 when Z² is HET(--R³, --R⁵); r' is 1when Z² is CONR³ ; Q¹ and Q² are independently --COOR³, tetrazole,--COOR⁶, --CONHS(O)₂ R¹³, --CN, --CONR¹² R¹², --CHO, --CH₂ OH, --COCH₂OH, --NHS(O)₂ R¹³, --C(O)R¹⁹, --NR¹⁷ C(O)OR¹⁷, --NR¹² C(O)NR¹² R¹²,--NHC(O)R¹⁸, --OC(O)NHR¹², --S(O)₂ R¹⁸, --S(O)R¹⁸, --S(O)₂ NR¹² R¹²,--NO₂, ##STR20## X¹ is O, S, --S(O)--, --S(O)₂ --, --NR³, or --CR³ R³--; X² and X³ are independently O, S, S(O), S(O)₂, or CR³ R¹⁶ ; Y is--CR³ ═CR³ --, --C═C--, --CR³ R³ --X¹ --, --X¹ --CR³ R³ --, --CR³ R³--X¹ --CR³ R³, ##STR21## Z¹ and Z² are independently --CONR³ --or--HET(--R³, --R⁵)--, provided that at least one of them is --HET(--R³,--R⁵)--; HET is ##STR22## substituted phenyl, benzyl, or 2-phenethylmean 1 or 2 substituents on the aromatic ring selected from C₁ -C₆alkyl, R¹⁰, NO₂, SCF₃, halogen, --COR⁷, --COR¹⁰, CN, and CF₃ ;and thepharmaceutically acceptable salts thereof.
 2. A compound of claim 1wherein the substituents are as follows:

    __________________________________________________________________________     ##STR23##                         I'                                         R.sup.1                                                                           Y        A             B                                                  __________________________________________________________________________    7-Cl                                                                              CHCH     S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                          (2,5-Thio)CO.sub.2 H                                                          7-Cl                                                                              CH.sub.2 O                                                                             S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                          (3,5-Pye)CO.sub.2 H                                                           7-Cl                                                                              CHCH     S(CH.sub.2).sub.2 C(O)N(CH.sub.3).sub.2                          (3,5-Pye)CO.sub.2 H                                                           __________________________________________________________________________     ##STR24##                                                                     ##STR25##                                                                


3. A compound of claim 1 whichis:5-((3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)(2-(dimethylcarbamoyl)ethylthio)methyl)thiophene-2-carboxylicacid;5-((3-((7-chloro-2-quinolinyl)methoxy)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)-3-pyridinecarboxylicacid, sodium salt; or3-(1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-1-((2-carboxy-4-pyridinyl)thio)methyl)benzoicacid.
 4. A compound of claim 1 wherein:R¹ is H, halogen, C₁ -C₈ alkyl,--CF₃, --SR², --S(O)R², --S(O)₂ R², --OR³, or --CN; R² is C₁ -C₈ alkylor --CF₃ ; R⁴ is H, --OR³, --SR³, NR³ R³, or C₁ -C₈ alkyl; R⁵ is H,halogen, --CN, --SR², --OR³, C₁ -C₈ alkyl, or --(C═O)R³ ; R¹³ is C₁ -C₈alkyl, --CF₃, or unsubstituted phenyl, benzyl, or 2-phenethyl; m and m'are independently 0-4; p and p' are independently 0-4; m+n+p is 1-10when X² is O or S; m'+n'+p' is 1-10 when X³ is O or S; Q¹ and Q² areindependently --COOR³, tetrazole, --COOR⁶, --CONHS(O)₂ R¹³, --CONR¹²R¹², or --NHS(O)₂ R¹³ ; X¹ is O, S, --NR³, or --CR³ R³ --; X² and X³ areindependently O, S, or CR³ R¹⁶ ; Y is --CR³ ═CR³ --, --C═C--, --CR³ R³--X¹ --, or --X¹ --CR³ R³ --;and the pharmaceutically acceptable saltsthereof.
 5. A compound of claim 1 wherein:R¹ is H, halogen, C₁ -C₈alkyl, --CF₃, --SR², --S(O)R², --S(O)₂ R², --OR³, or --CN; R² is C₁ -C₈alkyl or --CF₃ ; R⁴ is H, --OR³, --SR³, NR³ R³, or C₁ -C₈ alkyl; R⁵ isH, halogen, --CN, --SR², --OR³, C₁ -C₈ alkyl, or --(C═O)R³ ; R¹³ is C₁-C₈ alkyl, --CF₃, or unsubstituted phenyl, benzyl, or 2-phenethyl; m andm' are independently 0-4; p and p' are independently 0-4; m+n+p is 1-10when X² is O or S; m'+n'+p' is 1-10 when X³ is O or S; Q¹ and Q² areindependently --COOR³, tetrazole, or --CONR¹² R¹² ; X¹ is O, S, --NR³,or --CR³ R³ --; X² and X³ are independently O, S, or CR³ R¹⁶ ; Y is--CH═CH--; Z¹ and Z² are HET(--R³, --R⁵);and the pharmaceuticallyacceptable salts thereof.
 6. A pharmaceutical composition for preventingthe action of leukotrienes in a mammal comprising a therapeuticallyeffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 7. A method of preventing the action of leukotrienesin a mammal which comprises administering to said mammal an effectiveamount of a compound of claim
 1. 8. The method of claim 7 wherein themammal is man.